Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH3:87][O:88][C:89](=[O:93])[C@@H:90]([CH3:92])[NH2:91]>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:91][C@H:90]([CH3:92])[C:89]([O:88][CH3:87])=[O:93])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](C)N
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: COC(=O)[C@@H](C)NC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 143.3 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (622 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with D-alanine methyl ester hydrochloride (283 mg) in a similar manner as described in Example 24-(i) to give the titled compound (622 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of methyl (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D33, 2.5 g, 7.6 mmol), and diisopropylethyl amine (2 ml, 11.4 mmol) in dry DCM (25 ml) at 0° C. was added dropwise benzyl chloroformate (1.3 ml, 9.1 mmol) and the mixture was stirred for 1 h from 0° C. to r.t. The mixture was washed with a 20% solution of citric acid and after with brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (85:15) to afford the title compound (3.4 g, 97%) as a white solid; Rt (HPLC) 6.56 min; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.42-7.60 (m, 3H); 7.29-7.42 (m, 3H); 7.15-7.25 (m, 3H); 7.06-7.15 (m, 1H); 6.86-7.03 (m, 3H); 5.10 and 5.15 (s, s, 2H); 4.84-5.04 (m, 3H); 4.48 and 4.55 (m, m, 1H); 3.69 and 3.84 (s, s, 3H); 2.27-2.39 (m, 1H); 2.16-2.27 (m, 1H); 2.03-2.16 (m, 1H); 1.91-2.03 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].O>CC(C)=O>[C:1]([CH2:3][CH:4]([OH:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16])#[N:2]
Reactant: N#CCC(O)Cc1cccc(C(O)c2ccccc2)c1
Solvent: O
Solvent: CC(C)=O
Product: N#CCC(O)Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.08 h

Procedure:
7.35 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydride per 100 ml was added with stirring at 0° C to 7.8 g of 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in 78 ml of acetone and the mixture was allowed to stand at 0° C for 5 minutes and was then poured into water with stirring. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 7.4 g of 3-(3'-cyano-2'-hydroxypropyl)-benzophenone which was used as is for the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C:9](/[CH:17]=[CH:18]/[C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:23]=2)=[N:8]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:44]([C:46]1[C:51]([Cl:52])=[CH:50][N:49]=[CH:48][C:47]=1[Cl:53])[CH3:45])(=O)=O>C(#N)C>[Cl:53][C:47]1[CH:48]=[N:49][CH:50]=[C:51]([Cl:52])[C:46]=1[C@H:44]([O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[C:9]2/[CH:17]=[CH:18]/[C:19]1[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:23]=1)[CH3:45]
Reactant: C[C@H](OS(C)(=O)=O)c1c(Cl)cncc1Cl
Reactant: Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 3-neck 250 mL round bottom flask equipped with an internal temperature probe, reflux condenser, nitrogen blanket and magnetic stir bar, slurry (E)-1-(tetrahydro-2H-pyran-2-yl)-3-(2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazol-5-ol (10.0 g, 22.83 mmol) and cesium carbonate (7.88 g, 23.94 mmol) in ACN (92 mL) and warm to 60° C. To the suspension, add (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (7.03 g, 26.02 mmol) and stir overnight. Cool the reaction mixture to RT, filter and wash solids with ACN. Concentrate the filtrate and purify the residue by silica gel chromatography (2-4% (2 M ammonia in methanol)/DCM). Combine product fractions and concentrate in vacuo to a white foam. Yield: 12.5 g (86%). MS (ES) m/z 612 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3cscn3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 4-(tributylstannyl)-1,3-thiazole (0.12 g, 0.31 mmol, Synthonix) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was heated to 110° C. for 2 hours, then at 100° C. overnight. Solvent was removed in vacuo and the residue was dissolved in MeCN and filtered, then purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (35 mg, 34%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].[Li+].CCC[CH2-].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1cccc(C)n1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cccc(C)n1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of 2-ethynyl-6-methyl-pyridine (0.5 g, 4.3 mmol) in tetrahydrofuran (20 mL) is cooled to −78° C. and treated with 1.6 M N-butyllithium in hexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 h. This solution is then treated with ethyl chloroformate (2.85 mL, 30 mmol) and stirred for 3 h while the solution warms to room temperature. The reaction is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The solvent is removed to yield 0.67 g (83%) of desired product as a light yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CCO.O>[NH2:26][C:24](=[O:25])[CH2:23][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:27])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[CH3:22]
Reactant: COC(=O)COc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(CC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Yield: 62.5 %

Procedure:
A solution of 100 mg (0.245 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 2.0 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH to give 54 mg (57% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, mp, 225°-227° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[C:3]([OH:8])=[O:29].[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:28]([C:24]3[S:23][CH:27]=[CH:26][N:25]=3)(=[O:30])=[O:29])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C(F)(F)F
Product: O=S(=O)(c1nccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (150 mg, 0.457 mmol, published PCT patent application no. WO 2006/094842) was suspended in 20 mL of CH2Cl2. To this was added 2-thiazolesulfonyl chloride (84 mg, 0.457 mmol, Bioorg. Med. Chem., 2006, 14, 6628) and Hünig's base (0.2 mL). After stirring for 20 min at room temperature, the reaction was concentrated and then re-dissolved in methanol (3 mL). The crude material was purified by reverse-phase preparative HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), eluting with a 0.1% TFA in CH3CN/H2O, gradient (0% to 100% over 20 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (36 mg) as a white powder. 1H NMR (300 MHz, CD3OD) δ 8.09 (d, J=3.1 Hz, 1H), 8.01 (d, J=3.1 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.9 Hz, 2H), 3.44 (m, 4H), 3.35 (m, 4H). m/z (ESI, +ve ion) 476.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.664 μM; GK-GKRP EC50 (LC MS/MS)=0.842 μM.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[C:7]([O:11][C:12](=[O:15])[NH:13][NH2:14])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([NH:13][N:14]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCC(=O)CC
Product: CCC(CC)=NNC(=O)OC(C)(C)C

Procedure:
B-20a is prepared analogously to B-19a starting from 3-pentanone (1.23 mL, 11.6 mmol) and tert-butylcarbazate (1.53 g, 11.6 mmol). Yield: 2.26 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.[CH2:18]([Li])CCC.CCCCCC.CI>O1CCCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:18])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: Cc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution 5-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 10.0 g, 32.2 mmol) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (2.5 M, 19.3 mL, 48.2 mmol) dropwise. After stirring for 20 min at −78° C., methyl iodide (13.72 g, 96.6 mmol) was added. The resulting mixture was stirred for 2 h, quenched with a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2×200 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to give 1-(tert-butyl-dimethyl-silanyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine (7.92 g, 100%) which was used in the next step without purification: LC/MS m/e calcd for C14H22N2Si [M+H]+ 247.43, observed 247.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:4]=1.CO[CH:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:20]=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=3)[C:24](=[O:32])[NH:23][C:22]2=[O:33])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1cc(O)c(OCCN2CCCC2)cn1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1cc(O)c(OCCN2CCCC2)cn1

Procedure:
A mixture of 2-aminomethyl-5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ol (237 mg, 1.0 mmole), 3 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (329 mg, 1.0 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in methanol and purified by HPLC (acetonitrile/water without trifluoroacetic acid); the fractions belonging to the product peak (as determined by MS) were evaporated and still had impurities. This is re-purified by HPLC (acetonitrile water with 0.2% trifluoroacetic acid). The product is isolated by evaporation in-vacuo to give a yellow-orange solid assumed to be the bis trifluoroacetic acid salt, 30 mg, (4%); MS (ES +): m/z 535.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:8][C:7]2=[O:26])([OH:3])=O.Cl.[NH2:28][CH2:29][C:30]([NH2:32])=[O:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([CH2:29][NH:28][C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1)[CH2:8][C:7]2=[O:26])=[O:3])(=[O:31])[NH2:32]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)O)ccc1O2
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)NCC(N)=O)ccc1O2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Tert-butyl 6-carboxy-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (7.50 g, 20.8 mmol), glycinamide hydrochloride (2.76 g, 24.9 mmol), EDCI (4.78 g, 24.9 mmol), HOBT (3.78 g, 24.9 mmol), and TEA (5.80 ml, 41.6 mmol) were suspended in DMF (75 ml) and stirred at room temperature for 23 h. After removal of the solvent, the residue was diluted with EtOAc and H2O.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CO
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (5.0 g, 17.7 mmol) and dimethylpiperidin-4-ylamine (2.7 g, 21.2 mmol) in DCE (100 mL) was stirred at room temperature for 4 hours then triacetoxyborohydride (5.6 g, 26.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (2×70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was precipitated from IMS to give [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]dimethylamine as a white solid (4.45 g, 64%). LCMS (Method B): RT 0.37 min and 1.85 min; [M+H]+ 396
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C.N[C:17]1[C:21]([C:22]#[N:23])=C[NH:19][N:18]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:19]2[N:18]=[CH:17][C:21]([C:22]#[N:23])=[C:14]2[N:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Reactant: N#Cc1c[nH]nc1N
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cc(Cl)ccc3Cl)ccnc12
Yield: 92.5 %

Procedure:
A mixture of 98.3 g of 2',5'-dichloro-3-dimethylaminoacrylophenone and 43.5 g of 3-aminopyrazole-4-carbonitrile in one liter of glacial acetic acid was heated at reflux for 63/4 hours. The reaction mixture was cooled and diluted with water to provide a precipitate which was collected, washed with water and dried in vacuo to give 107.6 g of 7-(2,5-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as pale yellow crystals, mp 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH2:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[S:12]>O1CCCC1>[SH:12][C:11]1[NH:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[N:1]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)cc(F)c1N
Solvent: C1CCOC1
Product: Fc1cc(F)c2[nH]c(S)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A mixture of 1,2-diamino-3,5-difluorobenzene (1 g, 6.94 mmol) and 1,1′-thiocarbonyldiimidazole (2.05 g, 11.52 mmol) in 10 ml of tetrahydrofuran is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is then dried over MgSO4, filtered and concentrated under reduced pressure to yield 763 mg of 2-mercapto-4,6-difluorobenzimidazole. Yield=61%. Analytical LC/MS (method B): retention time=2.49 min. m/z=186.95 (positive ion mode).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:17])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
Under an argon atmosphere, to 4-trifluoromethylphenylacetic acid (51) (817 mg, 4.00 mmol) was added thionyl chloride (5.00 mL, 68.9 mmol), and heated to reflux (100° C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-trifluoromethylphenylacetyl chloride (52) as a brown oily crude product, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][C:22]1[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[S:24][N:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:19])[CH3:20])[C:9]=2[S:8][C:7]=1[CH:27]([C:26]1[C:22]([CH3:21])=[N:23][S:24][C:25]=1[CH3:29])[OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2C(C)C
Reactant: Cc1nsc(C)c1C=O
Product: CCOC(=O)c1c(C(O)c2c(C)nsc2C)sc2c1c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared by the method of example 15 part a) using 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester, and 3,5-dimethyl-4-isothiazolecarboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.[C:42]([O-:45])([O-])=[O:43].[K+].[K+]>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:42]([OH:45])=[O:43].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)ccc1Cl
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 15.4 %

Procedure:
4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (127.8 mg, 0.36 mmol) was dissolved in 3 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (144.0 mg, 0.72 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 3-bromopyridine (68.3 mg, 0.432 mmol) was added, followed by anhydrous K2CO3 (50.0 mg, 0.36 mmol). Then the vial was capped and microwaved at 250° C. for 30 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (15.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[SH:10])[C:5]#[N:6].[CH2:11]([OH:13])[CH3:12]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[O:13][CH2:11][CH3:12])[CH:7]=[CH:8][C:9]=1[SH:10]
Reactant: CCO
Reactant: N#Cc1ccc(S)c(Br)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(S)c(Br)c1
Reaction time: 0.5 h

Procedure:
3-Bromo-4-mercaptobenzonitrile (10 g) was dissolved in toluene (50 ml) and chloroform (80 ml), followed by adding thereto ethanol (3.0 ml), and the resulting mixture was cooled to −10° C. Hydrochloric acid gas was bubbled into the mixture through a bubbler for 10 minutes and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was allowed to stand in a refrigerator for 60 hours and then the completion of the reaction was confirmed by HPLC(ODS-A212). Dry nitrogen was bubbled into the reaction solution through a bubbler for 20 minutes and the hydrochloric acid gas was distilled off. The precipitate was collected by filtration, washed with toluene/chloroform and then dried to obtain ethyl 3-bromo-4-mercaptobenzene-carboximidate (13.6 g) as a light-yellow solid.