Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:8][CH2:7]2)=[O:10])=[CH:14][CH:15]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-fluoro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2C) (0.10 g, 0.38 mmol), 2-chloro-5-fluoro-pyrimidine (0.05 g, 0.38 mmol) and triethylamine (0.11 mL, 0.75 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S.(M+1):363.31
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(NS(=O)(=O)CCc2ccc(Cl)cc2)c(S(N)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(O)ccc1NS(=O)(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-ethanesulfonylamino]-5-methoxy-benzenesulfonamide (4.0 g, 9.90 mmol) in DCM (250 mL) at −78° C., BBr3 (1M in DCM, 70 mL, 70 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to warm to RT and the stirring was continued overnight. The reaction mixture was then cooled to −78° C., quenched by addition of methanol (20 mL) and water (50 mL), and the product was extracted with ethyl acetate. The organic extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from methanol to the title compound (3.45 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].Cl.[OH:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:14][N:15]=[C:6]([NH2:7])[C:5]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)cc(C(N)=NO)c1
Yield: 33.3 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-19 by using 3,5-dimethoxy benzonitrile (1.00 g, 6.13 mmol), hydroxyl amine HCl (0.634 g, 9.23 mmol) and potassium carbonate (2.53 g, 18.40 mmol), ethanol (20 mL) to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.75 (s, 6H), 5.79 (s, 2H), 6.49 (s, 1H), 6.84 (s, 2H), 9.62 (br s, 1H); MS (m/z): 197.11 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.[Pd]>[C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(CCc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1

Procedure:
37.7 g (0.1 mol) of the 4-diphenylamino-4'-methoxystilbene prepared in Synthesis Example 1-1 was dissolved in 250 ml of dioxane. To the thus obtained mixture, 4 g of 5% Pd/C powder and then 2.4 l of hydrogen were added. A solvent was distilled away from the reaction mixture, whereby 1-(4-diphenylaminophenyl)-2-(4-methoxyphenyl)ethane was obtained as an oily transparent compound of light yellow in color.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([CH3:23])([CH3:22])[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH:12]=2)[NH:7][C:6]=1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)[CH3:4].S([O-])([O-])(=O)=O.[Mg+2].[CH:38](=O)[CH2:39][CH2:40][CH3:41].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:38]([NH:1][CH2:2][C@H:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([CH3:23])([CH3:22])[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])[CH:12]=2)[NH:7][C:6]=1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)[CH3:4])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC=O
Reactant: CCN(CC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCNC[C@@H](C)c1c(-c2cc(C)cc(C)c2)[nH]c2ccc(C(C)(C)C(=O)N(CC)CC)cc12
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethylisobutyramide in dry chloroform at 0° C. is added magnesium sulfate followed by butyraldehyde and the mixture stirred at low temperature. After 30 minutes, a solution of sodium borohydride in methanol is added and the reaction allowed to proceed at 0° C. After completion, the reaction is quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion is washed with saturated aqueous sodium bicarbonate and then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C1COCC1>[CH3:11][C:12]([S@:15](/[N:17]=[C:8](/[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=1)\[CH3:9])=[O:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(C)c1
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a stirred solution of 1-(3-methylphenyl)ethanone (1.61 g, 12.0 mmol, 1.00 equiv.) and (R)-(+)-2-methyl-2-propanesulfinamide (1.94 g, 14 mmol, 1.33 equiv.) in THF (50 mL) was added Ti(OEt)4 (3.19 g, 14 mmol, 1.17 equiv.) dropwise. The reaction mixture was stirred for 16 h at 60° C., cooled to room temperature, and quenched with a saturated aqueous NaHCO3 solution (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×100 mL). The combined organics were concentrated and the resulting residue was purified by flash chromatography (silica gel, eluting with 0-5% CH3OH in CH2Cl2) to afford 1.51 g (53%) of the title compound as a white solid. LC/MS: m/z (ES+) 238 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[N:30]=1>>[CH3:36][C:31]1[N:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:34]=[C:33]([CH3:35])[N:32]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)nc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)nc(C)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyrimidine in Step 4. LC-MS Method 2 tR=1.073, m/z=464.1; 1H NMR (CD3OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.82 (m, 2H), 2.15 (m, 1H), 2.23 (m, 2H), 2.38 (m, 1H), 2.46 (s, 3H), 2.62 (s, 3H), 3.08 (m, 1H), 3.39 (m, 2H), 5.51 (m, 1H), 6.95-7.08 (m, 4H), 7.21 (m, 2H), 7.51 (s, 1H), 7.83 (d, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: COCCOCC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)COCCOC)C3)cc1

Procedure:
Compound dz was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-(2-methoxyethoxy)acetyl chloride. LC-MS: m/z=+513 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:25])[CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.[OH-].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+]>C1COCC1.O.O.O.O.O.O.O.[Co](Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:25])[CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3ccccc3F)cc2)S1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Cc2ccc(OCC(O)c3ccccc3F)cc2)S1
Yield: 63.2 %

Procedure:
To a stirring mixture of 5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (0.52 g, 1.40 mmol) in THF/H2O (1:1, 16 ml) was added 1M NaOH (2 ml), cobalt (II) chloride hexahydrate (0.2 mg, 0.0009 mmol), 2,2′-bipyridine (50.8 mg, 0.33 mmol), and finally sodium tetrahydroborate (0.11 g, 2.90 mmol). The reaction turned a deep blue/purple color. After a short time, the dark color began to fade and HOAc was added dropwise to regenerate the darker color. When the color faded and addition of HOAc failed to regenerate it, NaBH4 was added to regenerate the darker color. Added small portions of NaBH4 and HOAc dropwise until deep blue color persisted. After repeating this several times, HPLC indicated that the reaction was complete despite the fact that the deep blue color has given way to a light brown solution. The reaction was partitioned between water and EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 35% EtOAc/hexanes. Fractions containing compound were combined and evaporated in vacuo to give 0.32 g of the title compound as a white solid. MS (ESI−) for C18H16FNO4S m/z 360.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[N:4]([CH:20]([CH3:22])[CH3:21])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].C(O)C.[H][H]>[C].[Pd].C(N(CC)CC)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[CH:6]=[N:5][N:4]([CH:20]([CH3:22])[CH3:21])[C:3](=[O:23])[CH:2]=1
Reactant: COc1ccc(CNc2cnn(C(C)C)c(=O)c2Cl)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CNc2cnn(C(C)C)c(=O)c2)c(OC)c1

Procedure:
320 mg of 4-chloro-5-(2,4-dimethoxybenzylamino)-2-i-propyl-3(2H)pyridazinone (Compound No. 97), 50 ml of ethanol, 1 ml of triethylamine and 100 mg of palladium-carbon were stirred, and hydrogen was added to the mixture at a temperature of from 40° to 50° C. for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 230 mg of the above identified compound having a melting point of from 167 to 168° C.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[O:6]([C:13]([NH:15][O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:6]([C:13]([N:15]([CH:3]([C:2]#[CH:1])[CH3:4])[O:16][C:17]([O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: C#CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a 0° C. solution in THF (200 mL) of 3-butyn-2-ol (3.00 g, 42.9 mmol), N,O-bis(phenoxycarbonyl)hydroxylamine (11.7 g, 42.9 mmol), and triphenylphosphine (11.7 g, 42.9 mmol), was added dropwise diethylazodicarboxylate (7.40 g, 42.8 mmol). The reaction mixture was stirred for 2 hours at 0°-5° C. and then was concentrated almost to dryness. The residue was diluted with ethyl acetate, the solids were filtered off, and the flitrate was concentrated in vacuo. Chromatography on silica gel (5% ethyl acetate, pentane) provided N,O-bis(phenoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (12.3 g, 88% ).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH:25][C:46](=[O:48])[CH3:47])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COC(c2ccccc2)(c2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
Dissolve (R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (0.163 g, 0.31 mmol) in tetrahydrofuran (4 mL). Add triethylamine (0.044 g, 0.44 mmol) and acetic anhydride (0.036 g, 0.35 mmol). Stir 90 minutes and dilute with ethyl acetate (50 mL). Wash with 0.1 N aqueous citric acid, water, and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 10:90 to 50:50 ethyl acetate:hexanes to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[S:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[C:8]=2[C:20](OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[C:34]1(=O)[CH2:39][CH2:38]C[CH2:36][CH2:35]1.P(=O)(O)(O)O.C([SiH](CC)CC)C>C(O)(=O)C>[CH:20]1([C:8]2[C:9]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][C:10]=3[NH:11][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:38][CH2:39][CH2:34][CH2:35][CH2:36]1
Reactant: CCOC(=O)c1cc2c(C(=O)OC(C)(C)C)c(-c3ccccc3)[nH]c2s1
Reactant: O=C1CCCCC1
Agent: CC[SiH](CC)CC
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution (0.2 M) of 4-tert-butyl 2-ethyl 5-phenyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxylate in acetic acid was treated with acetic anhydride (2.5 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. overnight, then it was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was dissolved in TFA and cooled to 0° C. The resulting solution (0.1 M) was treated with triethylsilane (2 eq.) and stirred at 0° C. for 1 h then solvent was evaporated to give a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (58%) as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCNC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 25.9 %

Procedure:
The title compound (11 mg, 26%) was prepared as a tan solid from {4-[(ethylamino)carbonyl]phenyl}boronic acid (19 mg, 0.1 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 36 mg, 0.1 mmol), Pd(PPh3)2Cl2 (10 mg, 0.01 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.09 (t, 1 H, J=5.4 Hz), 4.98-4.84 (m, 1H), 4.20 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.61-3.41 (m, 2H), 2.87-2.71 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.32-1.13 (m, 11H); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:21]=1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:20][C:17]([C:14]1[CH:15]=[CH:16][C:8]2[NH:7][C:6]3[CH:21]=[C:2]([NH:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[CH:3]=[CH:4][C:5]=3[C:11](=[O:12])[NH:10][C:9]=2[CH:13]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(O)c1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reactant: Nc1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc2c(c1)NC(=O)c1ccc(Nc3ccncc3)cc1N2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A mixture of Example 189A (60 mg, 0.20 mmol), 4-aminopyridine (26 mg, 0.24 mmol), Pd2 (dba)3 (9.2 mg, 0.01 mmol), CyMAP (11.8 mg, 0.03 mmol), and Cs2CO3 (78 mg, 0.24 mmol) in 2 mL of dioxane was heated at 85° C. overnight. After the reaction mixture cooled to room temperature, it was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 100:5:1 EtOAc/MeOH/NH4OH to provide 54 mg (75%) of the desired product. MS (DCI) m/e 361 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.01 (s, 1H), 8.29 (d, J=4.68 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J=8.73 Hz, 1H), 7.09 (d, J=1.87 Hz, 1H), 6.99-7.03 (m, 3H), 6.86-6.89 (m, 2H), 6.63 (dd, J=8.58, 2.03 Hz, 1H), 4.68 (s, 1H), 1.36 (m, 6H).
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[Mg].Cl[CH2:6][C:7]1[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=1.S(=O)(=O)(O)O>C(OCC)C>[F:14][C:13]([F:15])([F:16])[C:9]1[CH:8]=[C:7]([CH2:6][CH2:3][CH2:2][OH:1])[CH:12]=[CH:11][CH:10]=1
Reactant: C1CO1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: OCCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of 57 g of oxirane in 120 ml of diethyl ether is added dropwise, at 0° to 10° C., to a Grignard solution prepared from 14.8 g of magnesium and 100 g of 3-(chloromethyl)benzotrifluoride in 450 ml of diethyl ether. The mixture is subsequently stirred at room temperature for 1 hour and 300 ml of 10% strength sulfuric acid are then added, while cooling with ice. The organic phase is collected and extracted twice more with diethyl ether and the combined organic phases are dried over magnesium sulfate and distilled. 76.7 g of 3-(3-trifluoromethylphenyl)propan-1-ol of b.p. 85° to 95° C. under 0.02 mm Hg are obtained.
Reaction SMILES: N1C=CC=NC=1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:9]=1[N+:25]([O-:27])=[O:26].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:8]2[C:9]([N+:25]([O-:27])=[O:26])=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:11]=[CH:12][N:13]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1cncnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
General Procedure for the Addition of Amine to pyrimidine: (6-Chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (132 mg, 0.4 mmole), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.4 mmole, 1 eq) and K2CO3 (0.4 mmole, 1 eq) were dissolved in DMF, and the mixture was stirred at 60° C. for 1 hour. Final product was precipitated out with water to provide Compound B1 as a yellow solid (152 mg, 77%). 1H NMR (400 MHz CDCl3) δ (ppm): 10.8 (s, 1H), 9.18 (d, 1H), 8.17 (s, 1H), 7.90 (d, 2H), 7.85 (d, 2H), 4.39-4.32 (m, 1H), 4.02 (m, 2H), 3.01 (s, 3H), 2.95-2.90 (m, 2H), 2.00 (m, 2H), 1.57-1.50 (m, 2H), 1.46 (s, 9H). Exact mass calculated for C21H28N6O6S 492.18, LCMS (ESI) m/z 493.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:12]=[N:13][N:14](C4CCCCO4)[C:15]=3[CH2:16][CH2:17][CH:18]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].FC1C=C(C2C3C(CCC=2)=NN(C2CCCCO2)C=3)C=CC=1C#N.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CC#N>[NH:14]1[C:15]2[CH2:16][CH2:17][CH:18]=[C:10]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=3)[C:11]=2[CH:12]=[N:13]1
Reactant: N#Cc1ccc(C2=CCCc3c2cnn3C2CCCCO2)cc1F
Agent: N#Cc1ccc(C2=CCCc3nn(C4CCCCO4)cc32)cc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2=CCCc3[nH]ncc32)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
2-Fluoro-4-(1-tetrahydropyran-2-yl-6,7-dihydroindazol-4-yl)benzonitrile and 2-fluoro-4-(2-tetrahydropyran-2-yl-6,7-dihydroindazol-4-yl)benzonitrile (0.23 g, 0.71 mmol) and H2SO4 (0.08 mL, 1.43 mmol) are added to CH3CN (5.0 mL) and the solution is stirred at room temperature for 6.0 hours. Aqueous Na2CO3 is added to basify the reaction, which is then diluted with ethyl acetate, the layers separated, and the aqueous back extracted with ethyl acetate (3×). The organics are combined, dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by silica gel flash chromatography eluting with 99:1 CH2Cl2/MeOH to give the title compound (0.102 g, 60%). ES/MS m/z 240 (M+H).