Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:20][C:9]3([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]3)[CH2:8]2)[CH:6]=1.[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=1[CH:30]([O:32][C:33]1[C:34]([NH2:48])=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)[CH3:31].N#N.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>[NH2:48][C:34]1[N:35]=[CH:36][C:37]([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:20][C:9]4([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]4)[CH2:8]3)[CH:6]=2)=[CH:38][C:33]=1[O:32][CH:30]([C:23]1[C:24]([Cl:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[Cl:21])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(n3cc(Br)cn3)C2)C1
Reactant: CC(Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(Oc1cc(-c2cnn(C3CC4(C3)CN(C(=O)OC(C)(C)C)C4)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 90 °C
Yield: 44.9 %

Procedure:
tert-Butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (145 mg, 0.42 mmol) and (±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (268 mg, 0.63 mmol) were added to a round bottom flask. It was vacuumed and refilled with N2 (3 times). DME (2.0 mL) and a solution of Na2CO3 (2.0 M, 1.0 mL) were sequentially added. It was vacuumed and refilled with N2 (3 times). Pd(PPh3)2Cl2 (14.7 mg, 0.021 mmol) was added. It was degassed again refilled with N2 (2 times). The mixture was stirred at 90° C. (heating bath) for 16 hrs. The reaction mixture was cooled to room temperature and H2O (30 mL) was added. The aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to give black residue which was purified by CombiFlash (40 g silica gel column, Hexane/EtOAc) to afford (±)-tert-butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (106 mg, 45%) as a off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1.[C:17](OCC(Cl)(Cl)Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1.[C:17]([O:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[CH3:15])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)OCC(Cl)(Cl)Cl
Agent: CC(O)c1ccc(OC2CCCCO2)cc1
Solvent: CCOCC
Product: CCCC(=O)OC(C)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 91 %

Procedure:
To 120 ml of anhydrous diethyl ether was added 22.2 g (0.1 mole) of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethanol, 22.4 g (0.1 mole) of 2,2,2-trichloroethyl butyrate and 25.2 g of Lipase P, and the mixture was reacted with stirring at 25° C. for 90 hours. After the reaction mixture was filtered by suction to remove Lipase P, the filtrate was concentrated, and the concentrate was then purified by silica gel chromatography [ethyl acetate/n-hexane=1/4 by volume] to give 10.2 g of S-form of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethanol (yield: 92%) and 13.1 g of R-form of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethyl butyrate (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12](S(C3C=CC=CC=3)(=O)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Levorotatory (−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(phenyl)sulfonyl]piperazine (100 gm) is added to 30% hydrobromic acid in acetic acid (271 ml). The suspension is stirred at 25-30° C. for 1 hour, heated to 60° C. and maintained for 4 hours. Water (1000 ml) is added to reaction mass and cooled to 25-30° C. The precipitate formed is filtered off and washed with water (250 ml). Toluene (500 ml) is added to the aqueous layer and basified with 50% aqueous solution of sodium hydroxide. Toluene layer is separated, distilled under reduced pressure and the residue left is recrystallised from boiling hexane (160 ml). The solution is filtered and allowed to recrystallise first at ambient temperature, and then in an ice bath. The product is filtered off, washed with hexane and dried to obtain 55 gm of levorotatory (−)-1-[(4-chloro phenyl)phenylmethyl]piperazine [M.R: 89-93° C.; [α]D25=−15.6 (c=1, methanol); Chiral Purity by HPLC: 99.7%].
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=4)[C:30]#[N:31])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: N#Cc1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(C#N)c3)n2)c1
Yield: 61 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-hydrazino-benzonitrile according to the method described for Example 91 in 61% yield. MS: M=418.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:27])[C@@H:14]([N+:24]([O-])=O)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:27])[C@@H:14]([NH2:24])[CH2:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)[CH2:11][O:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])COC1(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
Combine (R)-4-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.13 g, 2.71 mmol) and nickel (II) chloride (0.58 g, 4.485 mmol) in dry methanol (30 ml) and add sodium borohydride (0.454 g, 12 mmol) over 1 minute. Stir the resulting mixture for 20 minutes and then add water (3 mL). Concentrate and dissolve the residue in ethyl acetate. Filter the black solution through a pad of Celite® and wash the filter cake with ethyl acetate. Wash the filtrate with water (twice), saturated aqueous sodium chloride, dry (magnesium sulfate), filter, and concentrate to give the desired compound as a white solid (920 mg, 95%).
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([C:22](O)=[O:23])#[C:18][C:19]([OH:21])=[O:20]>>[CH2:1]([N:7]1[C:22](=[O:23])[C:17](=[CH:18][C:19]([OH:21])=[O:20])[S:9][C:8]1=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCNC(=S)Nc1ccccc1
Product: CCCCCCN1C(=O)C(=CC(=O)O)SC1=Nc1ccccc1
Yield: 64.5 %

Procedure:
Prepared by the method described in Example 1 from N-hexyl-N'-phenylthiourea (3.4 g, 14 mmoles) and acetylenedicarboxylic acid (1.7 g, 14 mmoles). Recrystallization from acetonitrile gave the product (3.0 g), mp 145°-146° C.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH3:27]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH3:27])[N:15]([CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N(C)c3ccccc3)c2c1C

Procedure:
Using the method of Examples 118-133, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 353.2073.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[N:14][NH:13][C:8]=2[N:9]=[C:10](O)[CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:18])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)nc2[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc2[nH]ncc12
Temperature: 110 °C
Yield: 21 %

Procedure:
A mixture of 6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (116.4 g, 0.562 mol) and phosphorus oxychloride (500 mL) was heated at 110° C. for 6 hours then cooled to room temperature before being evaporated under reduced pressure. The residue was taken up in EtOAc and the precipitate filtered. The filtrate was neutralized using triethylamine (500 mL) and the resulting salt filtered. The filtrate was concentrated under vacuum and the residue subjected to silica gel column chromatography using a 9/1 mixture of toluene/EtOAc to afford the title compound as a yellow solid (26.3 g, 21%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].Cl.CN(C)[CH2:25][CH2:26][CH2:27]N=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH2:25][CH2:26][CH3:27])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSCC(CC(=O)O)C(=O)c1cccnc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCOC(=O)CC(CSCCNC(C)=O)C(=O)c1cccnc1
Yield: 74.9 %

Procedure:
A solution of 3-{[2-(acetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid (0.1 g), 1[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68.1 mg) and 4-dimethylaminopyridine (0.1 eq) in dimethyl formamide (2 mL) was stirred for 24 h. The solution was purified on preparative HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 0.085 g (75%) of the title compound; ESMS (M+1)+353.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([C:17]#[N:18])=[C:5]([S:19]C2C=CC=CC=2)[N:4]=1.[S-2].[Na+].[Na+].Cl>CN(C)C=O>[CH3:1][N:2]([CH3:26])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([C:17]#[N:18])=[C:5]([SH:19])[N:4]=1
Reactant: CN(C)c1nc(Sc2ccccc2)c(C#N)c(-c2ccccc2)c1C#N
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: CN(C)c1nc(S)c(C#N)c(-c2ccccc2)c1C#N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Under argon, 280 mg (0.79 mmol) of 2-dimethylamino-4-phenyl-6-phenylsulfanyl-3,5-pyridinedicarbonitrile (step 2) are dissolved in 3 ml of abs. dimethylformamide (DMF), and 204 mg (2.6 mmol) of sodium sulfide are added. The reaction mixture is stirred at 80° C. for 2 hours. 6 ml of 1 N hydrochloric acid are added to the mixture and the resulting yellow crystals are filtered off with suction, washed with water and petroleum ether/diethyl ether 1/1 and dried under reduced pressure overnight.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.[C:39]([C:46](OCC)=[O:47])#[C:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(O)C>[CH2:44]([O:43][C:41]([C:40]1[N:15]2[CH2:14][C@@H:13]([CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)[O:17][C:16]2=[N:18][C:46](=[O:47])[CH:39]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, in ethanol (10 mL) was added diethyl acetylenedicarboxylate (0.39 g, 2.29 mmol). The reaction mixture was heated at reflux for 14 hours and then stored in a freezer overnight. The reaction mixture was warmed to room temperature. The resulting crystalline solid was isolated by centrifugation and dried under vacuum at 60° C. to afford 427 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidine-5-carboxylic acid ethyl ester. [α]D25 −16.15 (c 0.52, CHCl3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([OH:16])=O)=[O:10].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>ClCCl.CN(C)C=O>[N:28]1([C:14]([C:13]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([CH:12]=2)[C:9]([O:8][CH3:7])=[O:10])=[O:16])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3-[(methyloxy)carbonyl]-4-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 49; 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 h. The solvent was removed. The residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of morpholine (609 mg, 6.99 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 h. Water (60 ml) was added and the mixture was extracted with dichloromethane (3×60 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product as colourless oil. The crude product was loaded onto a silica gel column and was eluted with dichloromethane/methanol=20:1 to yield the title compound as a colourless oil. 450 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:26]4[CH2:27][O:24][CH2:25]4)[CH2:19][C@@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of (S)-5-bromo-1-methyl-3-(5-(2-methylpiperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 191h (40.0 g, 106 mmol), oxetan-3-one (11.4 g, 159 mmol), NaBH3CN (10.0 g, 159 mmol), and zinc chloride (21.3 g, 159 mmol) in methanol (700 mL) was stirred at 50° C. for 5 hours. The mixture was added to water (100 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (200 mL×3). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 191i (35 g, 73%). MS: [M+H]+ 434.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH2:3][O:4][C:5]([N:7]1[CH2:13][CH:12]([NH:14]C(OC(C)(C)C)=O)[C:11](=[O:22])[N:10]([CH2:23][CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)=[O:6].[ClH:39]>O1CCOCC1>[ClH:39].[F:38][C:2]([F:1])([F:37])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH2:14])[C:11](=[O:22])[N:10]([CH2:23][CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)=[O:6]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(C(=O)OCC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the (RS)-5-(2-benzyloxy-ethyl)-3-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester with hydrochlorid acid (37%) in dioxane yielded quantitatively the title compound as a light yellow foam; MS (m/e): 438 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([N+:18]([O-:20])=[O:19])[CH:7]=1)[C:3]([OH:5])=[O:4]>C1(C)C=CC=CC=1>[F:21][C:2]([F:1])([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([N+:18]([O-:20])=[O:19])[CH:7]=1)[C:3]([O:5][C:6]([CH3:11])([CH3:7])[CH3:2])=[O:4]
Reactant: O=C(O)C(F)(F)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(F)(F)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 176.5 %

Procedure:
To a solution of 2-difluoro-2-(3-nitro-5-(pyridin-4-yl)phenyl)acetic acid 52.D (450 mg, 1.53 mmol) in toluene (5 mL) was added n,n-dimethylformamide di-tert-butyl acetal (1.47 mL, 6.12 mmol). The mixture was stirred at 50° C. for 1 hour, then concentrated and dried under vacuum. The residue was then dissolved in EtOAc (10 mL), to which was added 10% Pd/C (150 mg). The air was then evacuated out of the flask and replaced by hydrogen. The mixture was stirred at room temperature for 2 hours, filtered over celite and then concentrated to afford tert-butyl 2-(3-amino-5-(pyridin-4-yl)phenyl)-2,2-difluoroacetate 52.E (473 mg, 96% yield) which is used in the next step with no further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[N:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][CH:22]=4)=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1.O.[NH2:31][NH2:32]>O1CCCC1.C(OCC)(=O)C>[CH:5]1([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[N:26]=[CH:25][C:24]([C:27]([NH:31][NH2:32])=[O:29])=[CH:23][CH:22]=4)=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 0 °C

Procedure:
A mixture of thionyl chloride (2 ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylic acid (E196b) (200 mg, 0.59 mmol) was stirred at reflux for 1 hour. The reaction mixture was concentrated in vacuo to afford a crude residue. The residue was dissolved in tetrahydrofuran (5 ml), cooled to 0° C. and hydrazine hydrate (1.5 ml) in tetrahydrofuran (1.5 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate and washed with a saturated solution of sodium carbonate, water, brine and dried (magnesium sulfate). The organic layer was filtered and concentrated in vacuo to afford the title compound (D54); MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][CH:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]1=[O:13]>CCOCC.[Cu]I>[CH3:4][C:5]1([CH3:2])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]1=[O:13]
Reactant: CC1CCC(C)(C)CC1=O
Reactant: CI
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.2 g of magnesium shavings are suspended in 100 ml of absolute ether and treated dropwise with 13.5 ml of methyl iodide. After the addition of 100 ml of ether, the mixture is boiled at reflux for a further 3 hours until all magnesium has dissolved. The mixture is cooled to 0° C. and treated with 20.7 g of finely powdered copper (I) iodide. After stirring at 0° C. for 15 minutes, a solution of 10 g of 3,6,6-trimethyl-2-cyclohexanone in 40 ml of ether is added dropwise thereto and the mixture is stirred at 0° C. for a further 4 hours. Thereafter, the yellow suspension is poured into ice/2N hydrochloric acid, extracted several times with ether, the organic phase is dried and evaporated. The residue is distilled in a water-jet vacuum. There are obtained 9 g of 2,2,5,5-tetramethylcyclohexanone as a colorless liquid, b.p. 71°-74° C./15 mm.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ncccc1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ncccc1N
Reaction time: 18 h
Yield: 98.4 %

Procedure:
A solution of 3-azido-2-cyanopyridine (1.44 g, 9.9 mmol) in ethanol (100 ml) was hydrogenated over palladium on carbon (10%, 50 mg) at room temperature and 3.5 p.s.i for 18 h. The catalyst was filtered off over Celite and the filtrate was concentrated to leave the product (1.16 g). 1H NMR (d6-DMSO) 7.87 (1H, d), 7.33 (1H, dd), 7.22 (1H, d), 6.28 (2H, s).
Reaction SMILES: N1C2C(=C(C3N=[C:12]([N:22]4[CH2:27]COCC4)[C:13]4S[C:17](COC)=[CH:16][C:14]=4N=3)C=CC=2)C=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.N1C=CC=C(CCl)C=1>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:17][C:16]3[CH:27]=[N:22][CH:12]=[CH:13][CH:14]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3cccnc3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with 3-picolyl chloride to give 4-(2-chloro-6-((pyridin-3-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine. Suzuki coupling of 4-(2-chloro-6-((pyridin-3-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 7 was carried out via General Procedure A. Purification using column chromatography gave 319. NMR: CDCl3: 3.90-3.94 (4 H, m, CH2), 4.08-4.13 (4 H, m, CH2), 4.68 (2 H, s, CH2), 4.88 (2 H, s, CH2), 7.30 (1 H, dd, J 7.79 and 4.87, Ar), 7.44 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.57 (1 H, d, J 8.20, Ar), 7.71 (1 H, d, J 7.79, Ar), 8.28 (1 H, d, J 7.35, Ar), 8.58 (1 H, dd, J 4.80 and 1.47, Ar), 8.63 (1 H, d, J 1.86, Ar) and 9.02 (1 H, s, Ar). MS: (ESI+): MH+ 459.16