Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]([OH:30])[CH2:15][NH:16][C:17]([C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([I:29])[CH:25]=4)[O:20]3)=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.B.CSC>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]([OH:30])[CH2:15][NH:16][CH2:17][C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([I:29])[CH:25]=4)[O:20]3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc([C@@H](O)CNC(=O)[C@H]2CCc3cc(I)ccc3O2)cn1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1ccc(C)n1-c1ccc([C@@H](O)CNC[C@H]2CCc3cc(I)ccc3O2)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of (2R)-N-{(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 355, 7.67 mmol, 1 eq.) in THF (150 mL) at room temperature was added slowly borane-methyl sulfide complex (2M in THF, 38.4 mmol, 5.0 eq.). After completion of the addition, the reaction mixture was heated to reflux for 2 hours and was then cooled to room temperature. The excess borane was quenched by the dropwise addition of EtOH (9 mL) followed by the slow addition of 2 M HCl (40 mL). The resulting mixture was heated to reflux for 1 hour and was then allow to cool to room temperature. The mixture was basified with 1N NaOH and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, using a gradient of 1:4 hexanes:EtOAc to 1:10 MeOH:EtOAc). The product was obtained as a pale yellow oil in 63% yield. MH+=503.9, RT=3.23 min.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([S:8](/[N:10]=[CH:11]/[C:12]1[N:16]2[CH2:17][C@H:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[F:37])[CH2:19][CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2=[N:14][CH:13]=1)=[O:9])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[C:4]([S:8]([NH:10][CH:11]([C:12]1[N:16]2[CH2:17][C@H:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[F:37])[CH2:19][CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2=[N:14][CH:13]=1)[CH3:1])=[O:9])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(/C=N/S(=O)C(C)(C)C)cnc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 117.5 %

Procedure:
Methylmagnesium bromide (0.24 mL, 0.71 mmol) was added to a solution of tert-butyl [(6S,9R)-3-{(E)-[(tert-butylsulfinyl)imino]methyl}-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (117 mg, 0.24 mmol) in tetrahydrofuran (4 mL) at 0° C. After 5 min, the mixture was warmed to ambient temperature. After 1.5 h, additional methylmagnesium bromide (0.24 mL, 0.71 mmol) was added. After 1.5 h, the reaction mixture was cooled to 0° C. and quenched with saturated aqueous ammonium chloride and water. The mixture was extracted with ethyl acetate (3×). The organic extracts were washed with saturated brine, dried with magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→94% dichloromethane/methanol) gave the title compound (144 mg). MS 511.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C@@H:7]1[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1)=[O:5].[CH:27]1[C:32]([CH:33]=O)=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[O:37]1[C:29]2[CH:28]=[CH:27][C:32]([CH2:33][N:10]3[CH2:11][C@@H:7]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[CH2:8][C@H:9]3[C:12]([O:14][CH3:15])=[O:13])=[CH:31][C:30]=2[O:35][CH2:36]1
Reactant: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Reaction time: 0.75 h

Procedure:
A solution of methyl(2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (19b) (138 mg, 0.38 mmol), piperonal (58 mg, 0.39 mmol) and glacial acetic acid (225 μL, 3.93 mmol) in tetrahydrofuran (2.8 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (125 mg, 1.88 mmol) was added in small portions and stirring was continued for 45 min at the same temperature. After dilution with ethyl acetate (5 mL), the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution (2×5 mL) and brine (5 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 100% dichloromethane and dichloromethane-ethylacetate (4:1, v/v) to give the title pyrrole (20):
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[Br:20][C:21]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:25]([C:32]([F:35])([F:34])[F:33])=[CH:24][C:22]=1[NH2:23]>N1C=CC=CC=1>[Br:20][C:21]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:25]([C:32]([F:33])([F:34])[F:35])=[CH:24][C:22]=1[NH:23][S:16]([C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])(=[O:18])=[O:17]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Br
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Solvent: c1ccncc1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2Br)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 3.9 %

Procedure:
2,4,6-Triisopropyl-benzenesulfonyl chloride (0.491 g, 1.59 mmol) was added to a solution of 2-bromo-3,5-bis(trifluoromethyl)aniline (0.483 g, 1.59 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (100 mL) and the mixture was washed with 0.1 N HCl (3×30 mL) followed by 0.1 N NaOH (2×30 mL) then saturated NaCl (2×30 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was purified by silica gel chromatography using hexanes/ethyl acetate (10:1) to afford the title compound (0.036 g, 4% yield). LCMS (M+Na) 597.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10](O)(=[O:12])[CH3:11]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NNc1ccc(I)cc1
Product: CC(=O)NNc1ccc(I)cc1

Procedure:
A mixture of 10 g of 4-iodophenylhydrazine in 80 ml of acetic acid is refluxed for 5 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, and the precipitate formed is filter-dried and washed with a propan-2-ol/PE (50/50; v/v) mixture. 9 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10]([NH:12][C:13](=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])SC)#[N:11]>>[C:10]([NH:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:11]
Reactant: NCCCCCCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCCCCCCN
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
1,7-Diaminoheptane (5.2 g) was warmed gently until molten and to it was added N-cyano-N'-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]-S-methylisothiourea (2.69 g). After stirring for 15 hours at room temperature the reaction mixture was extracted with ether to remove excess of the diamine starting material and then purified on a silica gel chromatographic column, eluting with isopropanol to give the title compound (1.08 g), m.p. 84°-87° C. (Found: C, 55.0; H, 8.2; N, 27.8; S, 9.0% C16H29N7S requires: C, 54.7; H, 8.3; N, 27.9; S, 9.1%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][C:10]([I:13])=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Ic1cnc(N2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)nc1

Procedure:
In 100 ml of methylene chloride was dissolved 13 g of 2-piperazin-1-yl-5-iodopyrimidine which was then reacted with 15 g of triphenylmethyl chloride at room temperature for 1 hour in the presence of 16 ml of triethylamine with stirring. The reaction mixture was added with methylene chloride, after which the organic layer was washed with water and brine, dehydrated, filtered and concentrated under vacuum. The residue was purified by use of ethyl acetate and a small quantity of methanol to obtain the title compound. 10 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C:12](O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: Cc1cc(Cl)nnc1NN
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)nn2c(C)nnc12
Temperature: 115 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
6-chloro-3-hydrazinyl-4-methylpyridazine (Step 111.1) (721 mg, 4.55 mmol) was dissolved in AcOH (15 mL, 262 mmol) and the resulting mixture was heated up and stirred at 115° C. for 1 hr. The reaction was cooled down to RT, diluted with CH2Cl2 and poured into a saturated aq. NaHCO3 solution. The aq. layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title product (752 mg, 3.91 mmol, 84% yield) as grey solid. tR: 0.59 min (LC-MS 2); ESI-MS: 183 [M+H]+ (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1c[nH]c2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylindole (1.19 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1.5 h the mixture was heated to 55° C. After a further 1.5 h the mixture was cooled and the resulting precipitate collected and washed with cold ethanol. Recrystallisation twice from ethyl acetate and once from ethanol gave the title pyrimidinone (660 mg), m.p. 228°-229° C., λmax (EtOH) 240 nm (ε 16,370) 300.5 nm (ε 13,090).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:13]([C:15](Cl)=[O:16])[C:12]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:7]=1[C:8](Cl)=[O:9].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:8](=[O:9])[C:7]3[C:6]([C:2]1=2)=[CH:14][C:13]1[C:15](=[O:16])[C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:12]=1[CH:11]=3
Reactant: O=C(Cl)c1cc(-c2cccs2)c(C(=O)Cl)cc1-c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=c1c2cc3c(cc2c2sccc12)c(=O)c1ccsc13
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A solution of 2,5-dithien-2-ylterephthalic acid chloride (4.38 g, 11.93 mmol) in DCM (100 cm3) is added to a suspension of anhydrous AlCl3 (5.0 g, 37.5 mmol) in DCM (100 cm3) at 0° C. The resulting mixture is further stirred for 30 minutes, then at 23° C. overnight. The reaction mixture is poured into ice-cold 2M HCl solution. The precipitate is collected and washed with 2M HCl and water then dried in vacuo, to yield the product as a deep blue solid (2.91 g, 83%). MS (m/e): 294 (M+, 100%), 281, 266, 207, 193; IR: v(cm−1) 1704 (C═O).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:13][CH2:12]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Li+].Cl>CO.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:14]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:13][CH2:12][CH:11]([CH2:10][S:7]([CH:5]([CH3:6])[C:4]([OH:35])=[O:3])(=[O:9])=[O:8])[CH2:16][CH2:15]2)(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
The product from Example 73 (55 mg, 0.1 mmol) was dissolved in methanol (2 mL) and lithium hydroxide (12 mg, 0.5 mmol) added. The reaction was stirred at room temperature overnight, diluted with water, acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (x3). The organic extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give a white solid (48 mg).
Reaction SMILES: [CH2:1]([P:3](Cl)([CH2:5][CH3:6])=[O:4])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:17][O:18][C:19]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:20]=1[CH2:21][N:22]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:23]([C:25]1[C:26](=[O:37])[N:27]([CH3:36])[C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:20]=1[CH2:21][N:22]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:23]([C:25]1[C:26](=[O:37])[N:27]([CH3:36])[C:28]2[C:33]([C:34]=1[O:35][P:3]([CH2:5][CH3:6])([CH2:1][CH3:2])=[O:4])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24]
Reactant: COc1ccc(CN(C(=O)c2c(O)c3ccccc3n(C)c2=O)c2ccccc2)c(OC)c1
Reactant: CCP(=O)(Cl)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCP(=O)(CC)Oc1c(C(=O)N(Cc2ccc(OC)cc2OC)c2ccccc2)c(=O)n(C)c2ccccc12
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
Diethylphosphorylchloride (150 mg, 0.87 mmol) was added to a solution of EtNiPr2 (129 mg, 1.00 mmol), DMAP (10 mg, 0.08 mmol) and N-(2,4-dimethoxybenzyl)-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (222 mg, 050 mmol) in CH2Cl2 (3.0 mL). The reaction mixture was stirred for 30 min and was then concentrated at reduced pressure. The residue was purified by silica column chromatography (EtOAc) to give the title compound (196 mg, 68%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=3[Cl:23])[CH2:16][CH2:15]2)[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=1.[CH3:25][N:26](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.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:24][C:19]1[CH:18]=[C:17]2[C:22](=[C:21]([Cl:23])[CH:20]=1)[N:14]([C:4]1[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=[C:2]([C:25]#[N:26])[N:3]=1)[CH2:15][CH2:16]2
Reactant: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCC(CC)n1cc(C#N)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Temperature: 175 °C
Yield: 21 %

Procedure:
A solution of 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) (100 mg, 0.23 mmol), zinc cyanide (32 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium(0) (32 mg, 25 μmol) in dimethylforamide (3 ml) was degassed with nitrogen and heated to 175° C. in a microwave for 5 min. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×2). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a crude residue. Purification by HPLC (reverse phase C18, 95% water in acetonitrile containing 0.1% trifluroacetic acid to 5% water in acetonitrile containing 0.1% trifluroacetic acid, flow rate 18 ml/min, retention time 38.4 min) gave the product (18 mg, 21%) as a yellow solid. mp 197-199° C.; 1H NMR (300 MHz, CDCl3): δ 7.27 (s, 1 H), 7.19 (d, J=2.2 Hz, 1H), 7.14 (d, J=1.8 Hz, 1 H), 4.82-4.77 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.15 (t, J=7.7 Hz, 2 H), 1.92-1.78 (m, 2 H), 1.75-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C18H19N4OCl2 (M+H)+: 377.0936; Found m/z 377.0910.
Reaction SMILES: [CH2:1]1CCCCC1.Cl[C:8]([C:14]1[C:19]([F:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=1[F:23])([CH3:13])[C:9]([F:12])([F:11])[F:10].C[Al](C)C>CCCCCC>[F:23][C:15]1[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[C:19]([F:20])[C:14]=1[C:8]([CH3:1])([CH3:13])[C:9]([F:12])([F:11])[F:10]
Reactant: C1CCCCC1
Reactant: COc1cc(F)c(C(C)(Cl)C(F)(F)F)c(F)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Yield: 97 %

Procedure:
To a cyclohexane (100 ml) solution of 2-(1-chloro-2,2,2-trifluoro-1-methylethyl)-1,3-difluoro-5-methoxybenzene (8.84 9, 32.2 mmol) was added 1.0 M hexane solution of trimethylaluminum (129 ml, 129 mmol) at room temperature and the mixture was stirred under reflux condition for 4 hours. Then, the reaction was quenched with 2 N-hydrochloride aqueous solution and the product was extracted with hexane which was dried over sodium sulfate, filtration and evaporation to furnish 7.9 g (97% yield) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)[CH2:15][C:14](=[O:27])[NH:13][C:12]=3[CH:28]=2)=[CH:4][CH:3]=1>[Ni]>[NH2:24][C:20]1[CH:19]=[C:18]([C:16]2[CH2:15][C:14](=[O:27])[NH:13][C:12]3[CH:28]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=3[N:17]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Agent: [Ni]
Product: Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 8-(4-fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo [b][1,4]diazepin-2-one (Example 67) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a light yellow solid (16 mg).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH:25]1([C:23]2[C:22]3[CH:21]([N:28]([CH:30]4[CH2:31][CH2:32]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:34])[C:17]=3[CH:16]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:35])=[O:3])=[CH:12][CH:11]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(C=CC(=O)O)cc3)cc(C3CC3)c21
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of 3-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylic acid ethyl ester (Intermediate 164, 0.08 g, 0.17 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with 2M sodium hydroxide solution (2 mL, 4 mmol) and the resulting reaction mixture was refluxed overnight. The reaction mixture was cooled to ambient temperature, the volatiles were evaporated in vacuo, the residue was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a solid (0.04 g, 50%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:15].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:15]
Reactant: COC(=O)c1ccc2c(c1)cc(C)n2C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2cc(CO)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1,2-Dimethyl-1H-indole-5-carboxylate (crude, 1.14 mg, 5.31 mmol) in THF (54 ml) Lithiumaluminium hydride (1 M in THF, 5.31 ml) was added at 0° C. The reaction mixture was stirred at rt for 2 hours. Sodium sulfate decahydrate was added to the reaction mixture to destroy the excess of Lithiumaluminium hydride. After 1 hour, methanol was added and the fine suspension was filtered off. The filtrate was concentrated under vacuum to afford crude (1,2-Dimethyl-1H-indol-5-yl)methanol. MS (Method V) [M+H]+=176.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:7]=[C:8]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (0.70 g) and pyridine (8 mL) was added thiophene-2-sulfonyl chloride (0.57 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.03 g, yield 93%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).