Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Br[CH2:21][CH2:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>O1CCCC1>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[CH:34][C:24]([O:23][CH2:22][CH2:21][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[CH:25][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 12.0 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 4.0 g of 2-(3-pyridyl)indole in 20 ml of tetrahydrofuran. The mixture is stirred for 0.5 hours at 0°-5° and then is added a solution of 5.06 g of ethyl p-(2-bromoethoxy)benzoate [for preparation see U.S. Pat. No. 2,790,825 (1957)] in 30 ml of tetrahydrofuran. The suspension is stirred at 0°-10° for 1 hour and at room temperature for 0.5 hour, poured into ice-water and extracted with ether. The ether extract is separated, dried over MgSO4, and concentrated to give 3-[2-(4-ethoxycarbonylphenoxy)-ethyl]-2-(3-pyridyl)-indole.
Reaction SMILES: CC([S@@]([NH:7][C@H:8]([C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O)(C)C.[ClH:26].O1CCOCC1>CO>[ClH:26].[CH3:25][C:24]1[C:19]([C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[NH2:7])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of (S)-2-methyl-N—((S)-(3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)propane-2-sulfinamide (0.355 g, 0.958 mmol) in MeOH (10 mL) was treated with hydrogen chloride, 4.0 M solution in 1,4-dioxane (0.6 mL, 2.400 mmol) and stirred at rt. The reaction was concentrated on the rotary evaporator resulting in a gummy residue. The residue (S)-(3-methylpyridin-2-yl)-(4-(trifluoromethyl)phenyl)methanamine hydrochloride was used in the next steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A solution of (S)-tert-butyl 4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoate (0.148 g, 0.312 mmol) in DCM (1.5 mL) was treated with trifluoroacetic acid (0.7 mL) at ambient temperature and stirring continued for 3 hours. The solvent was concentrated and the residue taken in water, neutralized with 1N NaOH carefully and suspended solids collected by filtration to afford (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)b enzoic acid (0.081 g, 62% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:28])[C@H:10]2[NH:14][C:15]2[S:16][C:17]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][N:19]=2)[C:7]=1[C:29]([O:31]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:28])[C@H:10]2[NH:14][C:15]2[S:16][C:17]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][N:19]=2)[C:7]=1[C:29]([OH:31])=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncc(C(=O)c4ccccc4)s3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3ncc(C(=O)c4ccccc4)s3)[C@H]2SC1

Procedure:
A 235 mg portion of (6R-trans)-3-[(Acetyloxy)methyl]7-[(5-benzoyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester was reacted with anisole and trifluoroacetic acid in dichloromethane as described in Example 5, giving 143 mg of the desired product as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][OH:21]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][OH:21]
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Reactant: NO
Agent: Cl
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 92 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 233.4 g (1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene, 100 g of 37% hydrochloric acid, 200 ml of water and 69.5 g (1.0 mol) of hydroxylamine hydrochloride are used. Working up and subsequent distillation yields 245 g (0,92 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal oxime; yield 92% of theory; boiling point 158°-162° C./4 Pa; nD20 =1.4930.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([CH3:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([S:35]([N:34]([CH3:39])[CH3:33])(=[O:37])=[O:36])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([CH3:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)c(C)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1cc(N(S(C)(=O)=O)S(=O)(=O)N(C)C)c(C)cc1OC
Yield: 54.4 %

Procedure:
A mixture of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide (500 mg), triethylamine (823 mg), dimethylaminosulfonyl chloride (1.17 g), and methylene chloride (20 ml) is refluxed for 39 hours. The reaction mixture is washed with aqueous sodium hydrogencarbonate. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 0.5-1% methanol/methylene chloride. The eluate is evaporated to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-[N-(dimethylaminosulfonyl)methanesulfonamido]benzamide (351 mg) as an oil. This product is mixed with tetrahydrofuran (3 ml) and 10% sodium hydroxide (3 ml) and warmed at 80° C. for 1 hour. The reaction mixture is evaporated to remove the tetrahydrofuran, acidified with hydrochloric acid, made alkaline with sodium hydrogencarbonate, salted out with sodium chloride, and shaken with methylene chloride. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 3% methanol/methylene chloride. The eluate is evaporated to remove the solvent. The residue is washed with ether/isopropyl ether and filtered to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide (211 mg). The product is recrystallized from acetonitrile/isopropyl ether to give crystals melting at 129° to 129.5° C.
Reaction SMILES: N.[K].[N:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][O:13][CH:14]=[CH2:15].[Cl-].[NH4+]>C(OCC)C>[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:15][CH2:14][O:13][CH:12]=[CH2:11])=[CH:5][CH:4]=1
Reactant: Cc1ccncc1
Reactant: C=COCCCl
Agent: N
Agent: [Cl-]
Agent: [K]
Solvent: CCOCC
Product: C=COCCCc1ccncc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To stirred liquid ammonia (2 liters) was added ferric nitrate (0.1 gm) followed by potassium metal (20 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution gamma-picoline (46.6 gms) was added over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Vinyl chloroethyl ether (53 gms) was added as quickly as the exothermic reaction allowed and the mixture was stirred for a further 2 hours. Solid ammonium chloride (25 gms) was then added in small portions, followed by diethyl ether (1 liter). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield vinyl 3-(4-pyridyl)-prop-1-yl ether (61 gms, 75% conversion); b.p. 90°-96° C/1 mm Hg.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([CH2:16][C:17]2([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][NH:18]2)([CH3:15])[CH2:6]1.[OH-].[Na+].Cl>O1CCCC1>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:6][C:7]2([CH2:16][C:17]1([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][NH:18]1)[CH3:15]
Reactant: COC(=O)CN1CC(C)(CC2(S(=O)(=O)c3ccccc3)C=CC=CN2)c2cc(Cl)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(CC2(S(=O)(=O)c3ccccc3)C=CC=CN2)CN(CC(=O)O)c2ccc(Cl)cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 158 %

Procedure:
A mixture of {5-chloro-3-[2-(benzenesulfonyl)pyridin-2-ylmethyl]-3-methylindol-1-yl}acetic acid methyl ester (0.15 g) and tetrahydrofuran (1.3 mL) was treated with 5.0 M aqueous sodium hydroxide solution (1.7 mL), and the resulting mixture was stirred at 40° C. for 2 hours. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (2:3 to 9:1 by volume) to afford the title compound as a white solid (0.23 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH2:24][CH2:25][CH3:26])=[N:22][N:23]=[C:3]12.C(N(CC)CC)C.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[C:44](Cl)=[O:45]>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH2:24][CH2:25][CH3:26])=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:44]([C:35]2[CH:36]=[CH:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=2)=[O:45])[N:8]=1
Reactant: CCCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
In 20 ml of chloroform was dissolved 1.5 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-propyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine, and 0.47 g of triethylamine was added to the solution. A solution of 0.89 g of naphthalene-2-carbonyl chloride in 10 ml of chloroform was added dropwise to the mixture at not more than 10° C. The mixture was further stirred for 1 hour at room temperature and washed with 0.1N hydrochloric acid, 0.1N sodium hydroxide and a saturated solution of sodium chloride in order. Thereafter, the solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether. Ethanol was added to yield crystals, which were collected by filtration. The crystals were recrystallized from chloroform-ethanol to give 1.4 g of 4-(2-chlorophenyl)-2-ethyl-6-(2-naphthalenecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, m.p. 226°-227° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].C(=O)([O-])[O-].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)c2ccc(-n3ccnc3)cc2)n2c1ccc1ccccc12
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A mixture of 3-cyano-(4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline (8 mg, 0.025 mmol), pottasium carbonate (10 mg, 0.072 mmol) and imidazole (5 mg, 0.073 mmol) were heated in 500 μL of DMF overnight. The reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, washed with water (3×10 mL), saturated NaCl and the organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude was purified by chromatography (3% methanol/chloroform) to yield the title compound (6.9 mg, 75%). 1H NMR (CDCl3): 8.21 (dt, J=7.80, 1.20 Hz, 2H), 8.08 (d, J=8.72 Hz, 1H), 8.02 (s, 1H), 7.87 (dd, J=7.81, 1.82 Hz, 1H), 7.73 (m, 2H), 7.60 (m, 4H), 7.46 (s, 1H), 7.42 (t, J=1.24 Hz, 1H), 7.30 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)[CH:7]=[CH:6]2>CO>[NH2:16][CH2:15][CH2:14][N:13]([CH2:18][CH2:17][Cl:1])[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=2)[N:9]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Solvent: CO
Product: NCCN(CCCl)c1ccc2cc(Cl)ccc2n1
Reaction time: 1 h
Yield: 84 %

Procedure:
HCl (gas) was transferred into a solution of tert-butyl 4-(6-chloro quinolin-2-yl)piperazine-1-carboxylate (1.6 g, 4.6 mmol) in methanol (40 ml) at room temperature with stirring for 1 hour and then concentrated under vacuum to afford N-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine as a white solid (1.1 g, 84%). (ES, m/z): [M+H]+ 248
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([NH2:35])=[O:34]>CC#N>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:32][C:33]([NH2:35])=[O:34])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Yield: 82.9 %

Procedure:
Following the general method as outlined in Example 41, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 250 mg; 0.73 mmol), K2CO3 (274 mg; 1.98 mmol), and 2-bromoacetamide (274 mg; 1.99 mmol) and MeCN (20 mL), 241 mg (83%) of the title compound was obtained as a white solid after filtration and concentration.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.CN(C)C=O.C(Cl)(=O)OCC.[CH2:29]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][NH2:38])[CH2:30][CH3:31]>C(O)(C)C.C(N(CC)CC)C.CC(C)=O>[CH2:29]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][NH:38][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=1)=[O:13])[CH2:30][CH3:31]
Reactant: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)O)c2O1
Reactant: CCCN1CCCC1CN
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Reaction time: 19 h

Procedure:
To a solution of 5 g of 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid in a mixed solvent of 50 ml of dimethylformamide and 50 ml of acetone is added 6.5 ml of triethylamine and the solution is stirred. Under cooling at 15°-18° C. 2.2 g of ethyl chlorocarbonate is added dropwise for 10 minutes and the whole is stirred at room temperature for 40 minutes. Then, 3.3 of 1-propyl-2-aminomethylpyrrolidine is added and the reactant is stirred at room temperature for 40 minutes. After it is allowed to stand for 19 hours, excess triethylamine and acetone are distilled off and the resulting residue is slowly poured into 400 ml of water with stirring. Under ice-cooling, crystals are precipitated thoroughly and collected by suction filtration. The crystals are washed with water and dried. The filtrate, aqueous layer is further extracted with chloroform three times, and the extract chloroform layer is washed with aqueous sodium bicarbonate solution and water and dried. The chloroform is distilled off under reduced pressure and to the residue obtained is added isopropanol. Crystals are deposited and collected by suction filtration. Both the crude crystals are put together and recrystallized from isopropanol/methanol (1/1) to give crystals of N-(1-propyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 177°-180° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C:9]1[N:10]=[CH:11][C:12]([CH:21]=O)=[C:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][C:14]=12)=[O:8].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C([BH3-])#N.[Na+]>CO>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][CH2:21][C:12]2[CH:11]=[N:10][C:9]([C:7]([O:6][CH3:5])=[O:8])=[C:14]3[O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18][C:13]=23)=[CH:26][CH:25]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1ncc(C=O)c2c1OC(C)(C)OC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ncc(CNc2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
Acetic acid (50 μL, 0.87 mmol) was added to a mixture of 5-Formyl-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylic acid methyl ester [J. Org. Chem. 1999, 64, 4537] (220 mg, 0.87 mmol) and 4-fluoroaniline (125 μL, 1.3 mmol) in dry methanol (4 mL) and stirred at room temperature for 15 min. and sodium cyanoborohydride (72 mg, 1.3 mmol) was added. This mixture was stirred at room temperature for 3 h followed by evaporation of 90% of the methanol volume under reduced pressure. The residue was extracted with dichloromethane (3×25 mL) and the combined organic layers were dried (anh. Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel (methanol/dichloromethane, 0 to 10% methanol) to give 0.290 g of methyl 5-((4-fluorophenylamino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (compound 21a) (96%) as a white solid MS-ESI m/z 347 [MI-1]+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>C1CCCCC1.C(OCC)C>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCCO
Reactant: Br
Solvent: C1CCCCC1
Solvent: CCOCC
Product: OCCCCCCCCCCBr
Temperature: 30 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
87.8 g (0.50 mol) of 1,10-decanediol, 165.1 g of 48% strength hydrobromic acid and 2.5 l of high-boiling petroleum ether (b.p. 100-140° C.) were heated under reflux with vigorous stirring for 4 hours. A further 80.0 g of 48 strength hydrobromic acid were added, and the mixture was boiled for 5 hours. After cooling to 30° C., the phases were separated. The organic phase was washed first with a solution of 100 g of Na2CO3 in 500 ml of water and then with 2×500 ml of water. Removal of the solvent was followed by chromatography on 700 g of silica gel. The byproduct 1,10-dibromodecane was eluted with cyclohexane/diethyl ether (20:1). Chromatography with cyclohexane/diethyl ether (2:1) afforded 103.9 g (0.44 mol, 87%) of 10-bromo-1-decanol.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=O)[C:11]2[NH:10][C:9]([CH:14]([CH3:16])[CH3:15])=[N:8][C:7]=2[N:6]([CH2:17][CH3:18])[C:4]1=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12](=[S:20])[C:11]2[NH:10][C:9]([CH:14]([CH3:16])[CH3:15])=[N:8][C:7]=2[N:6]([CH2:17][CH3:18])[C:4]1=[O:5])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCn1c(=O)c2[nH]c(C(C)C)nc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1c(=S)c2[nH]c(C(C)C)nc2n(CC)c1=O

Procedure:
1,3-diethyl-8-isopropyl-xanthine (6.25 g, 25 mM) (J Amer Chem Soc 1953, 75, 114-5) and 6.8 g (30 mM) of phosphorus pentasulfide were refluxed in 86 ml of pyridine for 3 days. At 10-20° C., 33.5 ml of 2N NaOH are added with cooling. The solid was filtered off and washed with pyridine. The filtrate was evaporated in vacuo to dryness, the residue suspended in 50 ml of water, adjusted to pH 7.5, the solid collected, washed with water and dried. The product was redissolved in 30 ml NaOH, treated twice with 0.5 g of charcoal, filtered, and acidified with 5N HCl to pH 3. At 5° C., the solid was collected, washed and dried.
Reaction SMILES: Cl[C:2]1[S:6][C:5](=[N:7][C:8](=[O:10])[CH3:9])[N:4]([CH2:11][CH2:12][O:13][CH3:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C(O)C.C(OCC)(=O)C.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>[F:15][C:16]1[CH:17]=[C:18]([F:22])[CH:19]=[CH:20][C:21]=1[C:2]1[S:6][C:5](=[N:7][C:8](=[O:10])[CH3:9])[N:4]([CH2:11][CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: COCCn1cc(Cl)sc1=NC(C)=O
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCCn1cc(-c2ccc(F)cc2F)sc1=NC(C)=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A flask was charged with the product from Example 197A (10.2 g, 42.6 mmol), 2,6-difluorophenylboronic acid (8.08 g, 51.1 mmol), Na2CO3 (64.0 mL of a 2 M aqueous solution, 128 mmol) and PdCl2(PPh3)2 (1.5 g, 2.13 mmol) in 100 mL of DME/H2O/ethanol (7:3:2). The mixture was warmed to 85° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate: hexane to provide 11.5 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H) 3.27 (s, 3H) 3.71 (t, J=5.3 Hz, 2H) 4.37 (t, J=5.4 Hz, 2H) 7.17-7.24 (m, 1H) 7.38-7.48 (m, 1H) 7.64-7.74 (m, 1H) 7.88 (s, 1H); MS (ESI+) m/z 313 (M+H)+.