Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].C(O)(=O)C>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])/[CH:1]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(/C=C/c1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
In a 500 mL flask, 99.4 g (0.50 mol) of 4-bromoacetophenone and 53.0 g (0.5 mol) of benzaldehyde were initially charged and dissolved in 50 g of methanol. The mixture was admixed with 6.7 g (0.025 mol) of 15% strength aqueous sodium hydroxide solution carefully added dropwise at 20-25° C. and subsequently stirred for 3 h. The reaction mixture was neutralized with glacial acetic acid and filtered and the solid was dried in vacuo to obtain 107 g (351 mmol) of (2E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH2:25]([NH:27][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])[CH3:26]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: CCN
Product: CCNC(=O)c1cc(/C=C/c2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 74 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using ethylamine instead of isopropylamine, to the title compound (30 mg, 74%) which was obtained as a colorless gum. MS: m/e=355.0 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:22]=[C:15]3[C:16]([O:18]C(=O)[NH:20][C:14]3=[CH:13][CH:12]=2)=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:16](=[O:18])[C:15]2[C:14](=[CH:13][CH:12]=[C:11]([S:8](=[O:9])(=[O:10])[NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:22]=2)[NH2:20])[CH2:26][CH2:25]1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC3CCCCC3)cc2c(=O)o1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(C(=O)c2cc(S(=O)(=O)NC3CCCCC3)ccc2N)CC1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-cyclohexylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-cyclohexylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 167°-168° (from ethanol). The hydrochloride melts at 263°-264°.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH2:32])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[N:12][N:11]=2)[CH2:3]1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>N1C=CC=CC=1>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:43]([CH3:42])(=[O:45])=[O:44])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:34])=[O:35])=[N:12][N:11]=2)[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O

Procedure:
To a solution of 5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinamine (200 mg, 0.347 mmol) in pyridine (1 ml) was added, dropwise, methanesulphonyl chloride (0.054 ml, 0.695 mmol) and the mixture stirred at 20° C. for 18 hr. Water (10 ml) was added and the title compound was collected by filtration as a brown solid (106 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 78.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.054 g (79%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:31][O-:32].[Na+]>CO.CS(C)=O>[CH3:31][O:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (35 mg, 0.075 mmol) was reacted with sodium methoxide (0.5 M in methanol, 1.0 mL, 0.488 mmol) in a mixture of methanol (4 ml) and DMSO (0.5 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (15 mg, 43%).
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:6].[Cl-].[NH4+]>C(OC)(C)(C)C.O1CCCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([OH:6])([CH3:2])[CH3:4])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CI
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
The reaction flask was charged under argon with 3.45 g of magnesium (142 mmol). A solution of 21.16 g of methyl iodide (147 mmol) in 120 mL of tert-butyl-methyl-ether was added during 45 minutes at 45° C. under stirring. Then stirring was continued for 1 hour at 45° C. and then a solution of 27.12 g of 4-benzyloxyacetophenone (120 mmol) in 100 mL of tetrahydrofuran was added during 45 minutes, while a temperature of 45° C. was again maintained. Stirring at 45° C. was continued for 1.5 hours. After cooling to room temperature, the white suspension was poured into a mixture of 100 mL of 10% aqueous ammonium chloride and of ice and extracted with 150 mL of ethyl acetate. The aqueous phase was separated and extracted with 100 mL of ethyl acetate. The organic phase was washed with 120 mL of 20% aq. sodium chloride, combined, dried (MgSO4) and evaporated under reduced pressure to give 29.9 g of crude product as an oil which partially crystallised. The crude product was taken up in 30 mL of dichloromethane. The solution was concentrated at the rotary evaporator almost to dryness. Then 6 mL of ethyl acetate was added followed by gradual addition of a total of 180 mL of hexane. The suspension was then kept at 0° C. for 30 minutes. The crystals were collected and washed with cold hexane. After drying for 2 hours at 16 mbar/45° C., 26.7 g (92%) 2-(4-benzyloxy-phenyl)-propan-2-ol was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]1[CH:13]=[CH:14][N:15]=[C:7]1[C:6](=O)[NH:5]2.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]1[CH:13]=[CH:14][N:15]=[C:7]1[C:6]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[N:5]2
Reactant: NCCCO
Reactant: O=c1[nH]c2cc(F)c(F)cc2n2ccnc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(F)c(F)cc2n2ccnc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A mixture of 7,8-difluoroimidazo[1,2-a]quinoxalin-4(5H)-one (Eur. J. Med. Chem. 1998, 33, 943) (20 mg, 0.090 mmol), hexamethyldisilazane (66 μL, 0.31 mmol), ammonium sulphate (2.4 mg, 0.018 mmol) and 3-aminopropan-1-ol (34 μL, 0.45 mmol) was stirred under argon at 120° C. overnight. The reaction mixture was allowed to cool down to room temperature and the white residue was diluted in ethyl acetate and water. A white precipitate was filtered off and the filtrate was washed with brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 90/10) to afford the title compound as white crystals (4.5 mg, 18%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:20]([C:21](=[O:23])[CH3:22])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6′-acetylamino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-5b (36.9 mg, 0.11 mmol) and 1-bromomethyl-3-chloro-benzene (15.8 μL, 0.12 mmol) in DMF (1.1 mL) at room temperature was added 60% NaH in mineral oil (5 mg, 0.13 mmol). After stirring at room temperature for 4 h, the reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with H2O (3×10 mL), brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude material was purified by preparative TLC using 50% ethyl acetate/ether with 1% NH4OH to afford the title compound I-5c (27.1 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
3-[4-(4-Nitrophenoxy)pyridin-2-yl]-1,1-dimethylurea (607 mg) was dissolved in tetrahydrofuran (20 ml)-methanol (20 ml), and then 10% palladium carbon (236 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (529.5 mg, 96.7%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[C@H:22]([CH3:23])[CH2:21][CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@H:17]([OH:18])[C@@H:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][C@H:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CC[C@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CC[C@H](N=[N+]=[N-])[C@@H](O)CN1C(=O)OCc1ccccc1
Yield: 88.9 %

Procedure:
Sodium azide (0.139 g, 2.14 mmol) was added to a solution of (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) in MeOH (1.5 ml) and H2O (0.15 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.192 g, 89%): 7.39–7.30 (m, 5H), 5.15 (2H, s), 4.10–3.67 (m, 2H), 3.10 (1H, d), 1.85–1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)([O-:14])=[O:13]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Yield: 62.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-3 using 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 200 mg, 0.96 mmol), 4-(trifluoromethyl)phenol (233 mg, 1.43 mmol), K2CO3 (264 mg, 1.91 mmol) in CH3CN (5 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.85 (d, J=4.8 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.36 (d, J=7.2 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.82 (t, J=8.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 6.98 (d, J=5.4 Hz, 1H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I.Cl>[Cu]I.C(NCC)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6]
Reactant: C#CCCC(=O)O
Reactant: Brc1ccccc1I
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1Br
Reaction time: 2 h

Procedure:
To 10 ml of diethylamine was added with stirring 0.5g (5.1 mmol) of 4-pentynoic acid, 1.4g (5 mmol) of 1-bromo-2-iodobenzene, and 60 mg (0 05 mmol) of trakis(triphenylphosphine)palladium(0) The slurry was degassed with argon and 0.19 g (1.0 mmol) of CuI was added. The reaction mixture was stirred for 2 hr. at room temperature and then poured into approximately 100 ml of a 10% HCl solution. The resulting precipitate was filtered, washed with water and dried. The solid was taken up in hot CHCl3 and filtered to remove insoluble salts. After evaporation of the solvent, the resulting orange solid was recrystallized from a chloroform-hexane mixture to produce a tan solid, m.p. 87-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)(=[O:37])=[O:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(OC)c(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 292 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 3,4-dimethoxy benzene sulfonyl chloride. The compound of example 292 was used directly without isolation, for the preparation of compound of example 293.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:32])=[C:11]([C:9]([NH:8][CH:5]4[CH2:4][CH2:3][N:2]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+:27]([C:30]1[C:31]([S:36]Cl)=[N:32][CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>ClCCl>[CH2:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:36][C:31]1[C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)SSC[C@H](NSc1ncccc1[N+](=O)[O-])C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (60 mg, 0.201 mmol) and triethylamine (0.034 ml, 0.241 mmol) were dissolved in dichloromethane (1 ml), and the solution was cooled to 0° C. 3-Nitro-2-pyridinesulfenyl chloride (46.0 mg, 0.241 mmol) was added and the mixture was stirred at 0° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)—N-benzyl-3-(tert-butyldisulfanyl)-2-(((3-nitropyridin-2-yl)thio)amino)propanamide (Compound tk94) (87 mg, 96%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].ClCCl.[CH3:10][S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[C:27]([O:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:26]=[CH:25][N:24]=1)[CH2:18][CH2:17]2)(=[O:13])=[O:12]>O>[CH:1]([NH:4][C:5]([N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:27]2[CH:28]=[C:23]([N:19]3[C:20]4[C:16](=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:22][CH:21]=4)[CH2:17][CH2:18]3)[N:24]=[CH:25][N:26]=2)[CH2:35][CH2:34]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: CC(C)N=C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Isopropyl isocyanate (31 μL, 0.315 mmol) was added to a dichloromethane (5 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (78.1 mg, 0.209 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as white powder (87.3 mg, yield: 91%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[CH2:16]([NH:23][S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][S:24](/[C:27](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:28]#[N:29])(=[O:26])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)NCc2ccccc2)cc(C(C)C)c1O

Procedure:
The titled compound was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and N-benzyl cyanomethylsulfonamide under the similar conditions as described for EXAMPLE 12 (part B).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]3=[N:12][C:11]=2[C:25]#[C:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[C:47](Cl)(=[O:51])[O:48][CH2:49][CH3:50]>C1COCC1>[CH2:49]([O:48][C:47]([O:1][NH:2][C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:13]3=[N:12][C:11]=2[C:25]#[C:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][N:5]=1)=[O:51])[CH3:50]
Reactant: CCOC(=O)Cl
Reactant: N=C(NO)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)ONC(=N)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
A solution of compound 42a (0.16 g, 0.33 mmol), DIEA (0.17 g, 1.3 mmol) and ethyl carbonochloridate (0.10 g, 0.93 mmol) in THF (10 mL), was stirred at rt for 2 h. The reaction was then quenched with water (50 mL). The solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain compound 42b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H26N8O4: 563.2 (M+H). Found 563.2.