Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([C@@H]1[C@@H](CO)O[C@@H]([N:11]2[CH:19]=[C:17](C)[C:15](=[O:16])[NH:14][C:12]2=O)C1)=[N+]=[N-].F[C@@H]1[C@@H](CO)O[C@@H]([N:28]2C=C(C)C(=O)NC2=O)C1.FC1C(=O)[NH:40][C:41](=O)[N:42](C=1)[C@@H:43]1[O:51][C@H:48]([CH2:49][OH:50])[C@@H:46]([OH:47])[C@H]1O.C1NC2N([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=NC=2C(=S)N=1.OCCCOCN1C=NC2C(=O)NC(N)=NC1=2.C(OCN1C=NC2C(=O)NC(N)=NC1=2)C>>[CH:41]1[N:42]([CH2:43][O:51][CH:48]([CH2:49][OH:50])[CH2:46][OH:47])[C:19]2[N:11]=[C:12]([NH2:28])[N:14]=[C:15]([OH:16])[C:17]=2[N:40]=1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: CCOCn1cnc2c(=O)[nH]c(N)nc21
Agent: Nc1nc2c(ncn2COCCCO)c(=O)[nH]1
Agent: OC[C@H]1O[C@@H](n2cnc3c(=S)nc[nH]c32)[C@H](O)[C@@H]1O
Product: Nc1nc(O)c2ncn(COC(CO)CO)c2n1

Procedure:
3'-deoxy-3'-azidothymidine, 3'-deoxy-3'-fluorothymidine, 5-fluorouridine, 6-mercaptopurine-9-β-D-ribofuranoside, 6-methylmercaptopurine-9-β-D-ribofuranoside, 9-{[(1-hydroxymethyl)ethoxy]-methyl}guanine and 9- (ethoxymethyl)guanine.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]([F:33])[C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][C@H:18]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=4)[C:17]3=[O:32])[CH2:12][CH2:11]2)=[N:8][CH:9]=1>C1COCC1>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([F:33])[C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][C@H:18]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=4)[C:17]3=[O:32])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cl
Product: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.4 %

Procedure:
Aqueous 1 M LiOH (1.5 mL, 1.5 mmol) was added to a solution of (S)-methyl 5-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.17 g, 0.38 mmol) in THF (2 mL). The mixture was stirred overnight at ambient temperature. The THF was removed under vacuum and the resulting aqueous solution was adjusted to pH 1 via the addition of aqueous 1 M HCl. The resulting solids were collected by filtration and air-dried to afford (S)-5-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinic acid hydrochloride (0.13 g, 0.28 mmol, 74%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].C(N(CC)C(C)C)(C)C.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>ClCCl.O>[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][N:31]([C:47]([CH:44]2[CH2:46][CH2:45]2)=[O:48])[CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
To [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester hydrochloride (0.357 g, 0.736 mmol) and N,N-diisopropylethylamine (0.75 mL, 4.3 mmol) in dichloromethane (4 mL) was added cyclopropanecarbonyl chloride (0.074 mL, 0.814 mmol), and the reaction was stirred at room temperature. Once no starting material was seen by analytical LCMS, the mixture was diluted with dichloromethane and water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated, and the residue was purified by silica gel chromatography (ethyl acetate in hexanes gradient) to give the title compound.
Reaction SMILES: NC1C=CC(C)=C(NC2O[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)C=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34](=[O:36])C)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.NC1C=CC(C)=C(NC(=O)C)C=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]2[O:36][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reactant: COc1cc(NC(C)=O)cc(OC)c1
Agent: CC(=O)Nc1cc(N)ccc1C
Product: COc1cc(Nc2ncc(-c3ccc(C#N)cc3)o2)cc(OC)c1
Yield: 85 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(3,5-dimethoxyphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=85%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]=[N:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]4[NH:19][N:18]=[N:17][N:16]=4)[CH:22]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(Br)cc12
Yield: 47.6 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-bromo-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 10) (510 mg, 1.57 mmol) and [3-(1H-tetrazol-5-yl)phenyl]amine (230 mg, 1.4 mmol) giving 300 mg (27%) of the title compound. MS (ESI+) calcd for C16H12BrN5O2S2 448.961579, found 448.961839.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]#[N:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]1[NH:37][N:36]=[N:35][N:32]=1)[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(-c3ccccc3)ccc2-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)cc1
Yield: 30.8 %

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 48 mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). The solids were isolated by vacuum filtration and dissolved in methylene chloride. The organic solution was dried (MgSO4), filtered and the solvent removed under reduced pressure to give 5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H -tetraazole as an amorphous beige solid (0.203 g, 92%), mp 190–200° C. (dec). Elemental Analysis for C29H23N5O.0.49 H2O.0.21 C3H7NO Calc'd: C, 73.90; H, 5.32; N, 15.15. Found: C, 73.05, H, 5.25; N, 15.03.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].B.CSC.CO>C1COCC1>[OH:12][CH2:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](CO)CC1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.00 g, 26.9 mmol) in THF (30 mL) was added borane-dimethylsulfide complex (1.0 M in THF, 40 mL, 40 mmol) dropwise at 0° C. and then the mixture was stirred at 20° C. for 6 hours. Methanol (50 mL) was dropwise at 0° C., and then the reaction mixture was stirred at room temperature for 1 hour before being concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate. MS ESI calc'd for C9H12O3 [M+H]+ 173. found 173. 1H NMR: (400 MHz, DMSO-d6) δ 4.39 (br s, 1H), 3.57 (s, 3H), 3.21-3.18 (m, 2H), 2.22-2.20 (m, 1H), 1.91-1.87 (m, 2H), 1.74-1.73 (m, 2H), 1.31-1.27 (m, 3H), 0.91-0.76 (m, 2H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:34])([F:33])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]([O:30]CC)=O)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>O1CCCC1.CO>[F:3][C:4]([F:33])([F:34])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]([NH:2][CH3:1])=[O:30])=[O:25])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reaction time: 12 h

Procedure:
7.10 ml (14.15 mmol) of a solution of methylamine (2M) in tetrahydrofuran are added to a solution of 1.60 g (3.54 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{4′-[(trifluoro-methyl)oxy]-4-biphenylyl}-1-piperazinecarboxylate, prepared in step 1.3., in 14 ml of methanol. Stirring is continued at room temperature for 12 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. A solid is obtained, and is recrystallized from a mixture of ethyl acetate and diisopropyl ether. 0.86 g of pure product is thus obtained in the form of a white solid.
Reaction SMILES: C(OC1C=CC(N2CCOCC2)=CC=1C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.C([O:38][C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:44][C:40]=1[C:41]([NH2:43])=[O:42])C1C=CC=CC=1>>[OH:38][C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)=[CH:44][C:40]=1[C:41]([NH2:43])=[O:42]
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: O=C(OCc1ccccc1)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Product: NC(=O)c1cc(N2CCOCC2)ccc1O
Yield: 83 %

Procedure:
In a manner identical to Example 140, 121 mg (0.30 mmol) of benzyl 2-benzyloxy-5-(morpholin-4-yl)benzoate is converted to 2-benzyloxy-5-(morpholin-4-yl)benzamide which on hydrogenolysis gives 56 mg (0.25 mmol, 83% yield) of 2-hydroxy-5-(morpholin-4-yl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:28])=[N:26]O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:42][O:43][C:44](=[O:47])[CH2:45][CH3:46].O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[NH:28][CH:46]=[C:45]([C:44]([O:43][CH3:42])=[O:47])[N:26]=1)=[CH:14][CH:13]=2)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)OC
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=NO)ccc2c1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1c[nH]c(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
To a mixture of tert-butyl{6-[amino(hydroxyimino)-methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.47 g, 1.0 mmol) and triethylamine (0.17 mL, 1.2 mmol) in ethyl acetate (10 mL) was added methylpropionate (0.10 g, 1.2 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was poured into water (5 mL), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added p-xylene (10 mL), the mixture was refluxed for 40 h. The reaction mixture was diluted with ethyl acetate (100 mL), and the solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 (v/v)) to give methyl 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1H-imidazole-4-carboxylate (0.22 g, 42%) as an orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH:10]3[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:22][C:23]1[N:24]=[C:25]2[C:31]([N:32]=[C:33]=[O:34])=[C:30]([C:35](OCC)=[O:36])[S:29][C:26]2=[N:27][CH:28]=1>>[ClH:22].[ClH:22].[CH3:1][O:2][C:3]1[C:8]2[N:9]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]4[C:35](=[O:36])[C:30]5[S:29][C:26]6[N:27]=[CH:28][C:23]([Cl:22])=[N:24][C:25]=6[C:31]=5[NH:32][C:33]4=[O:34])[CH2:13][CH:10]3[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1sc2ncc(Cl)nc2c1N=C=O
Reactant: COc1cccc2c1N1CCN(CCCCN)CC1CO2
Product: COc1cccc2c1N1CCN(CCCCn3c(=O)[nH]c4c(sc5ncc(Cl)nc54)c3=O)CC1CO2
Product: Cl

Procedure:
The product from Example 11A and the product from Example 8D were processed as described in Example 1L to provide the title compound. mp 198-201° C.; [α]23D−7.8 °(c 1.02, DMSO); 1H NMR (300 MHz, DMSO-d6) δ1.60-1.85 (m, 4H), 2.80-3.75 (m, 7H), 3.78 (s,3H), 3.82-4.75 (m, 6H), 6.42-6.95 (m, 3H), 9.02 (s, 1H), 10.60 (bs, 1H), 1290 (s, 1H); MS (DCI/NH3) m/e 529 (M+H)+; Anal. calcd for C24H25N6O4SCl.2.0 HCl: C, 47.89; H, 4.52; N, 13.96. Found: C, 47.64; H, 4.62; N, 13.63.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[O:8][CH2:7][CH2:6][C@@H:5]2O.C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OC(=O)C)C>[N:28]([C@H:5]1[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1)=[N+:29]=[N-:30]
Reactant: O[C@H]1CCOc2c(Br)cc(Br)cc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCOc2c(Br)cc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution containing 6,8-dibromo-chroman-4(S)-ol in tetrahydrofuran (0.17M) and 1.2 equivalents of diphenylphosphorylazide was stirred for 15 minutes at room temperature. The solution was cooled to 10° C. and 2.5 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene added. The mixture was stirred with gradual warming to room temperature and maintained for 48 h. The mixture was diluted with ethylacetate and washed with brine followed by water. The organic phase was concentrated to afford the title compound as a tan oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22]>C(Cl)Cl.C(OCC)C>[ClH:22].[ClH:22].[CH3:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)ncn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(N2CCC(N)CC2)ncn1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of [1-(6-methyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (686 mg, 2.3 mmol) in CH2Cl2 (12 mL) was added at room temperature under stirring a 2 M HCl solution in diethyl ether (6 mL) and was stirred at room temperature over night. The precipitate was filtered off, washed with CH2Cl2 and diethyl ether and dried to yield the title compound as a light yellow solid (610 mg, 98%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:27]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:9]3[C:8]([CH3:7])=[CH:12][S:11][CH:10]=3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:29]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3cscc3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.26 mmol; 3 eq.), Intermediate 32 (120 mg; 0.42 mmol; 1 eq.), Intermediate 1 (70 mg; 0.42 mmol, 1 eq.) and DIEA (217 μL; 1.26 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) followed by crystallization from n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][O:17]1>>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:16](=[O:15])[O:17][CH2:18][CH2:19][C:20]=23)[C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc2c1CCOC2=O

Procedure:
N-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-acetamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=3[N:13]=2)[CH:8]=1.[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:18][C:14]1[C:12]2[N:13]=[C:9]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:19][CH2:20][O:21][CH3:22])[O:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1ccc(OC)cc1-c1nc2c(C)cccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
A mixture of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) (1.78 g, 5.95 mmol), N-bromosuccinimide (1.01 g, 5.95 mmol), and AIBN (82 mg, 0.5 mmol) in CCl4 (100 mL) was refluxed for 15 h under dry N2 gas flowing. The reaction mixture was cooled to 0° C., the precipitation was removed by filtration maintaining the temperature. After the solvent was evaporated, the residue was washed with small amount of ethanol several times to afford a pinkish solid (1.72 g, 76%). 1H-NMR (500 MHz, CDCl3) δ3.57 (s, 3H), 3.88 (s, 3H), 4.96 (s, 2H), 5.27 (s, 2H), 7.05 (dd, 1H, J=8.5, 3.0 Hz), 7.22 (d, 1H, J=8.5 Hz), 7.34 (t, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=1)=[O:9])=[O:5].C(N(CC)CC)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44].Cl>C1COCC1.CCOC(C)=O>[CH2:43]([NH:45][C:46]([NH:1][C:2]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=1)=[O:9])=[O:5])=[O:47])[CH3:44]
Reactant: CSc1ccc(C(=O)N[C@H]2CCCC[C@H]2NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2N)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCCC[C@@H]1NC(=O)c1ccc(SC)cc1
Reaction time: 72 h
Yield: 17.5 %

Procedure:
2-(amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide (Example 114a) (50 mg) was dissolved in THF (2.5 mL) prior to the addition of triethylamine (30 mg) and ethyl isocyanate (21 mg). After stirring for 72 h, EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) provided the title benzamide (10 mg). MS found: (M+Na)+=602.4.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:43])[NH:26][C:27]3[C:32]\2=[CH:31][C:30]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH3:56].[OH2:57]>CN(C=O)C>[NH2:56][C:1]([CH2:4][N:5]([C:10]1[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:43])[NH:26][C:27]3[C:32]\2=[CH:31][C:30]([NH:33][S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])=[CH:29][CH:28]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1)[S:6]([CH3:9])(=[O:7])=[O:8])=[O:57]
Reactant: O
Reactant: N
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC(N)=O)c1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 250 mg (0.4 mmol) of (Z)-3-[1-(4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone and 82 mg (0.4 mmol) of CDI in 5 ml of DMF is stirred for 1 hour at 50° C. 1 ml of condensed ammonia is added and the mixture is stirred for 5 hours at ambient temperature. Then water is added. The yellow precipitate is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1F

Procedure:
The title compound, light grey solid (75 mg, 90%), MS (ISP) m/z=334.5 [(M+H)+], mp 250.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).