Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:12](OC)(=[O:17])[C:13]([O:15][CH3:16])=[O:14]>C1COCC1>[CH3:16][O:15][C:13](=[O:14])[C:12]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:17]
Reactant: COC(=O)C(=O)OC
Reactant: Brc1cccc2cnccc12
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
Tert-BuLi (1.7 M pentane, 27.2 mL, 46.3 mmol) is added to dry THF (195 mL) at −78° C., after few minutes, a solution of 5-bromo-isoquinoline (6.42 g, 30.86 mmol) in THF (5 mL) is added via syringe dropwise. The resulting solution is allowed to stir at −78° C. for 45 minutes, then dimethyl oxalate (11 g, 93 mmol) is added in one portion. After 30 min at −78° C., the reaction is quenched using saturated ammonium chloride solution, diluted with 200 mL EtOAc, and then the TB is removed by rotovap. The residue is diluted with saturated ammonium chloride solution extracted with EtOAc (2×200 mL). The organic layers are combined and washed with 1×75 mL water and 1×75 mL brine, dried over anhydrous sodium sulfate, then concentrated. The material is then purified using flash column chromatography, 20% EtOAC/Hexanes, to yield 3.91 g, 59% of isoquinolin-5-yloxoacetic acid methyl ester. MS (ES, m/z): (M+30 1) 216.1
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][C:10]([OH:12])=O)[C:4]=1[CH3:13])=[O:2].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][C:10]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])[C:4]=1[CH3:13])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Reactant: NCCN1CCCC1
Product: Cc1[nH]c(C=O)c(C)c1CC(=O)NCCN1CCCC1

Procedure:
(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid was reacted with 1-(2-aminoethyl)pyrrolidine using General Amidation Procedure 1 to give 2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide. MS m/z 278 [M+1].
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])C.[OH-].[Na+]>CO>[CH3:21][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[S:10][C:6]=1[CH2:5][C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To ethyl{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}acetate (intermediate 13, 0.5 g) in methanol (5 ml) was added 2M sodium hydroxide solution (3 ml). The resulting suspension was stirred at room temperature for 40 minutes, before the solvent was removed in vacuo. The residue was diluted with water (5 ml) acidified (2M hydrochloric acid) and the product extracted twice with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to give the title compound as a yellow solid.
Reaction SMILES: O[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccccc23)c(C)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2,3-b]indolizine (10.1 g; 32 mmol) in phosphorus oxychloride (60 mL) is heated at 100° C. for 1 hour, cooled to room temperature, and concentrated in vacuo. The residue is partitioned into ice water and dichloromethane. The aqueous phase is separated and extracted twice with dichloromethane. The combined organics are washed with a 1 N aqueous sodium hydroxide solution and then with water. The solution is dried (Na2SO4), filtered, and concentrated in vacuo, and the resulting dark residue is filtered through a short pad of silica gel and washed with 25% ethyl acetate in hexane. The filtrate is concentrated in vacuo to give 10.1 g of the title compound as a yellow solid (94%): 1H nmr (400 MHz, CDCl3) d 2.00 (s, 6 H), 2.37 (s, 3 H), 2.64 (s, 3 H), 6.58 (t, 1 H), 6.95 (dd, 1 H), 7.00 (s, 2 H), 7.07 (s, 1 H), 7.08 (d, 1 H), 9.26 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+]>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[C:7]2[C:8](=[O:14])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2c(Br)cccc2O1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2cccc(Br)c2C1=O
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.013 mole) 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran, 10.7 grams (0.039 mole) of potassium persulfate, and 3.3 grams (0.013 mole) of copper(II) sulfate pentahydrate in 30 mL of water and 30 mL of acetonitrile is heated at reflux for one hour. After this time the reaction mixture is poured into 200 mL of water. The mixture is then extracted with one 200 mL portion of diethyl ether. The extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residual oil. The oil is subjected to column chromatography on silica gel. Elution is accomplished using 1:1 petroleum ether and methylene chloride. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2.1 grams of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:10]1[C:15](=[O:16])[C:14]2[N:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]1[C:29]2[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=2[S:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:10]1[C:15](=[O:16])[C:14]2[N:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:24][C:25]2[C:29]3[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=3[S:27][N:26]=2)[C:11]1=[O:21])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2cccnc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A mixture of 46 mg of (S)-2-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-butyric acid tert-butyl ester, 41 mg of 3-bromomethyl-4,6-dimethyl-1,2-benzoisothiazole and 111 mg of potassium carbonate is stirred at room temperature for 4 h. The reaction mixture is diluted with water and the product is filtered and washed with water. The isolated solid is purified by flash chromatography on silica gel to give 72 mg (99%) of (S)-2-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-butyric acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]2[N:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35][CH2:34][O:33]2)[CH:29]=[CH:30][CH:31]=1>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=4)[N:36]([CH2:35][CH2:34][OH:33])[CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: Clc1cccc(C2OCCN2Cc2ccccc2)c1
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(OC)c(O)c(C(c3cccc(Cl)c3)N(CCO)Cc3ccccc3)c1)O2
Yield: 26.6 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofuran and 32.8 g of 2-(3-chlorophenyl)-3-benzyl-1,3-oxazolidine are held in 260 ml of absolute alcohol for 60 hours at 70° C. and subsequently the solvent and excess of 2-(3-chlorophenyl)-3-benzyl-1,3-oxazolidine are removed, finally in vacuum. After purification by means of a chromatographic column there is obtained 9.8 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenyl-(3-chlorophenyl)-methyl)-N-(2-hydroxyethyl)-N-benzylamin, a bright yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:2]1.[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH:21]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[NH:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])=[O:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccsc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To an oven dried flask was charged with N-(thiophen-3-yl)pivalamide (2.0 g, 10.91 mmol) and THF (50 mL) at rt, then the light tan solution was cooled down to −78° C., followed by dropwise addition of n-BuLi (2.4M in hexanes, 9.60 mL, 24.01 mmol) over 5 min under N2. The resulting off-white suspension was stirred for 1 hr, followed by addition of DMF (3.21 mL, 41.5 mmol) through a syringe over 2 min. In 20 min, the suspension became tan solution and the reaction mixture was warmed to rt and continued stirring for 30 min. The conversion was completed as determined by TLC, thus the reaction was quenched with sat. NH4Cl, partitioned between Et2O/H2O (150 mL/50 mL), after separation, the organic solution was washed with brine, dried (Na2SO4), concentrated and purified on Biotage Fresh Collector eluting with 10˜40% EtOAc/Hexanes to afford the expected product, N-(2-formylthiophen-3-yl)pivalamide (1.85 g, 80%) as a tan oil. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 1.32 (s, 9 H) 7.68 (d, J=5.19 Hz, 1 H) 8.19 (d, J=5.19 Hz, 1 H) 9.71 (s, 1 H) 10.97 (s, 1 H); Mass spec. 212.09 (MH+) calc. for C10H13NO2S 211.07.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].Br[CH2:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42].C(N(CC)CC)C.O>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:40]([C:41]([F:44])([F:43])[F:42])([OH:45])[CH2:39][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(CBr)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1(O)C(F)(F)F
Temperature: 85 °C
Reaction time: 21 h
Yield: 44.5 %

Procedure:
To a solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (351 mg, 0.67 mmol) in butanone (6.7 mL) was added 3-bromo-1,1,1-trifluoroacetone (0.14 mL, 1.34 mmol) and triethylamine (0.19 mL, 1.34 mmol), and the reaction was stirred at 85° C. for 21 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel containing water (5 mL), and the aqueous mixture extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to provide a diastereomeric mixture (2:1) of the title compound as an orange solid (189 mg, 45%): mp 185-187° C.; 1H NMR (400 MHz, CDCl3, both diastereomers) δ 8.56 (m, 2H), 8.22-8.14 (m, 6H), 7.83-7.75 (m, 8H), 7.49-7.34 (m, 10H), 7.32-7.23 (m, 2H), 4.22 (s, 1H), 3.82 (dd, J=12.5, 4.8 Hz, 2H), 3.51 (d, J=13.2 Hz, 1H), 3.40 (d, J=12.3 Hz, 1H), 3.31 (s, 1H), 3.09 (tt, J=13.9, 7.0 Hz, 2H), 1.31-1.13 (m, 12H); 19F NMR (376 MHz, CDCl3) δ −58.02, −78.33, −78.77; ESIMS m/z 636 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10](B(O)O)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.[OH-].[Ba+2].[OH-].O>C(OCCCC)(=O)C.Cl>[F:32][C:28]1[CH:27]=[C:26]([C:10]2[N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:22])[N:4]([CH3:23])[C:3](=[O:24])[N:2]3[CH3:1])[CH:31]=[CH:30][CH:29]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCCCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Intermediate Ga Step 2) (7.31 g, 20.7 mmol), 1-bromo-3-fluorobenzene (2.10 mL, 18.8 mmol), Pd-118 (245 mg, 0.38 mmol), and barium hydroxide (6.44 g, 37.6 mmol) in n-butyl acetate (64 mL) was heated to 80° C. Water (4.06 mL, 226.0 mmol) was added and the mixture was stirred vigorously at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature diluted with 1M HCl(aq) (100 mL) and was extracted with DCM (3×100 mL). The combined organic layers were washed with saturated brine (1×100 mL), dried over magnesium sulfate and the evaporated under vacuum. The residue was recrystallised from methanol to afford the title compound.
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=NC=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C@@H:19]([CH:29]([CH3:31])[CH2:30][CH3:2])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CCC(C)[C@@H](CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
Intermediate I was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.88-0.95 (m, 6 H) 1.11-1.20 (m, 1 H) 1.34 (s, 9 H) 1.44-1.54 (m, 1 H) 1.64-1.72 (m, 1 H) 3.17-3.27 (m, 1 H) 3.33-3.43 (m, 1 H) 4.11-4.21 (m, 1 H) 4.81 (s, 1 H) 5.92 (d, J=8.20 Hz, 1 H) 8.05 (s, 1 H). LCMS (ESI) 407.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:7]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:11](=[O:28])[C:10]([CH:29]=[O:30])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6].Cl>C(O)(C)C>[CH2:3]([C:7]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:11](=[O:28])[C:10]([CH2:29][OH:30])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ccc(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCc1ccc(CO)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
15 mg of NaBH4 are added at 20° to a solution of 370 mg of 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3-formyl-1,2-dihydro-2-oxopyridine in 5 ml of isopropanol, with stirring. After further stirring (1 hour), dilute hydrochloric acid is added dropwise until the evolution of H2 has ceased, and the mixture is evaporated. 6-Butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3-hydroxymethyl-1,2-dihydro-2-oxopyridine is obtained after conventional working-up.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([NH2:25])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)[N:9]=[C:10]([C:23]#[N:25])[CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)nn2-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(-n2nc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A mixture of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxamide (1.3 g) and methanesulfonyl chloride (2.5 g) in pyridine (20 ml) was stirred at 50° C. for 5 hours. The solvent was evaporated, and dilute hydrochloric acid and ethyl acetate was added to the residue. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and methanol (20:1) to give crystals of 5-[4-(methylsulfonyl)phenyl]-1-[4-(methylsulfonyloxy)-phenyl]pyrazole-3-carbonitrile (0.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](OCC)=O)=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2.C(CP(=O)(OCC)OCC)#[N:42]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]#[N:42])=[CH:30][CH:31]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Product: CC/C(=C(/c1ccc(/C=C/C#N)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl

Procedure:
The title compound was prepared from (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde (Compound 193, Step 1) and diethyl (cyanomethyl)phosphonate following General Procedure E. LCMS: 428 [(M-THP+H)+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[C:26]([O:17][CH:14]2[CH2:13][CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:16][CH2:15]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1nccnc1Cl
Reactant: OC1CCN(c2ccc3ccccc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(quinolin-2-yl)piperidin-4-ol (see PREPARATION P1.1; 2.0 g, 8.7 mmol) in DMF (30 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.47 g, 17.4 mmol) at 0° C. The mixture was stirred at room temperature for 60 min and then 2,3-dichloro-pyrazine (1.2 g, 8.7 mmol) was added. The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (10% to 30% EtOAc in petroleum ether) to give the title product (2.0 g, 5.8 mmol, 70% yield) as white solid. ESI-MS (M+1): 341 calc. for C18H12ClN4O 340.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](F)=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CS(C)=O.CCOCC.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:19][C:16]2[CH:17]=[N:18][C:13]([C:12]([C:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH2:11][O:10]3)([F:20])[F:21])=[CH:14][CH:15]=2)=[N:27][CH:28]=1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Reactant: Fc1ccc(Cl)cn1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ccc(Cl)cn4)cn3)CO2)c(F)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (400 mg, 1.337 mmol) and 5-chloro-2-fluoropyridine (805 μL, 8.02 mmol) in dry DMSO (13.4 mL) was added cesium carbonate (871 mg, 2.67 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 75° C. for 2 h, then rt for 12 h. The reaction as heated to 75° C. for an additional 30 min then cooled to rt, diluted with Et2O and poured into a separatory funnel containing water. The aqueous layer was extracted with Et2O (3×) and then the combined organic layers were washed with 1:1 brine:H2O (3×) then once with brine and dried by passing through a phase separator. Volatiles were removed by rotary evaporation and the crude residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 10% EtOAc/Hexanes for 5 min then ramp to 25% over 8 min-paused gradient at 25%) to yield the title compound as a colorless oil (91 mg, 16.6%): 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=2.4 Hz, 1H), 8.14-8.07 (m, 1H), 7.72 (dd, J=8.7, 2.7 Hz, 1H), 7.57 (dd, J=8.6, 2.5 Hz, 1H), 7.52 (dd, J=8.6, 0.6 Hz, 1H), 7.40 (dd, J=14.7, 8.2 Hz, 1H), 7.00 (dd, J=8.6, 0.4 Hz, 1H), 6.88-6.82 (m, 1H), 6.76 (ddd, J=9.9, 9.0, 2.5 Hz, 1H), 3.46 (d, J=5.1 Hz, 1H), 3.03-2.96 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −106.83 (dd, J=257.5, 8.3 Hz, 1F), −107.38-−108.26 (m, 2F), −109.27 (q, J=8.4 Hz, 1F); ESIMS m/z 412 ([M+H]+).
Reaction SMILES: C(OC([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:29])[NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[N:21]([CH3:26])[C:20]([CH3:28])([CH3:27])[CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:17][CH:18]2[CH2:19][C:20]([CH3:27])([CH3:28])[N:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH2:23]2)=[O:29])=[CH:12][CH:11]=1)[NH2:8]
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NNC(=O)OC(C)(C)C)cc2)CC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Reaction time: 1.5 h

Procedure:
N′-[4-(1,2,2,6,6-Pentamethyl-piperidin-4-ylcarbamoyl)-phenyl]-hydrazinecarboxylic acid tert-butyl ester was dissolved in 4M HCl in dioxane (30 ml) and left to stir for 1-2 hrs. The solution went quickly from a deep orange colour to a bright orange colour. After 1 hr reaction time, the solvent was removed under vacuum to reveal an orange oil that under a vacuum for several minutes crystallized out to give orange crystals in a sticky orange oil. Yield: 4.68 g, 87%.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][NH2:13])[CH:3]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>CCO.Cl>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:4]2[CH:3]=[N:2][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cnc2ccccc2c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cnc3ccccc3c2)n1
Yield: 54.9 %

Procedure:
A mixture of 1-(quinolin-3-yl)hydrazine hydrochloride (4 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and conc. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-3-yl)-1H-pyrazol-5-amine (3.0 g, 55% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.16 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 5.72 (s, 1H), 5.45 (s, 3H), 1.23 (s, 9H).