Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=CC=1.CN(C)[C@@H]1CCN(C([C:28]2[CH:32]=[C:31]([CH3:33])N[C:29]=2[CH:34]=[O:35])=O)C1.[CH2:37](O)C>N1CCCCC1>[CH3:37][O:35][C:34]1[CH:29]=[CH:28][C:32]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:12]2=[O:18])=[CH:31][CH:33]=1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: CCO
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene](4-(4-methoxy-phenyl-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 81%).
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][C:17]4[CH:20]=[CH:21][O:22][C:16]=4[CH2:15]3)=[O:13])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)(=O)C>[CH3:25][N:26]([CH2:28][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:8]([C:6](=[O:7])[C:1]4[S:5][CH:4]=[CH:3][CH:2]=4)=[CH:24][CH:23]=3)[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH3:27]
Reactant: CNC
Reactant: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1cccs1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3cccs3)cc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.251 g (0.744 mmol) of 6-[4-(2-thenoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.10 g (1.1 mmol) of 50% aqueous dimethylamine and 0.09 g (1.1 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with an aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].N>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(Br)cccc1Br
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Temperature: 62.5 °C
Reaction time: 0.21 h
Yield: 83 %

Procedure:
A solution of 2,6-dibromopyridine 1-oxide (34.0 g, 0.13 mol) in sulfuric acid (120 mL) was cooled to 0-5° C. followed by addition of nitric acid (60 mL). The reaction mixture was stirred at the same temperature for 10-15 min then heated to 60-65° C. for 20 h. The reaction was then cooled to rt, poured into ice-cold water and neutralized with aqueous ammonia solution. The resulting solution was stirred for 10 min at 0-5° C. then filtered and dried to obtain the desired product as a pale yellow solid (32 g, 83%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:22]([CH3:23])=[CH:21][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[O:13])=[C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>COCCOC.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>[CH3:23][C:22]1[C:8]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:9][C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[N:17][CH:16]=1)=[O:13]
Reactant: Cc1cc(C(=O)Nc2ccnnc2)c(OCc2ccccc2)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Product: Cc1cc(C(=O)Nc2ccnnc2)c(OCc2ccccc2)cc1-c1cnn(C)c1
Temperature: 120 °C

Procedure:
Sodium carbonate (0.32 ml, 0.32 mmol) was added to 4-bromo-5-methyl-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 10; 64 mg, 0.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.1 mg, 0.19 mmol) and Pd(Ph3P)4 (11.14 mg, 9.64 μmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated in a microwave at 120° C. for 1 hour, the solvent was removed in vacuo and the solid triturated with DMSO/methanol (1:1, 1 ml) to yield the title compound as a white solid. 9 mg.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:8][C:6]1[C:5]([F:9])=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1nc(F)c(F)c(N2CCN(Cc3ccccc3)CC2)c1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
To a solution of pentafluoropyridine (1.76 ml, 16.0 mmol) and 1-benzylpiperazine (2.64 g, 15.0 mmol) in DMSO (20 ml) was added potassium carbonate (4.20 g, 30.4 ml). The suspension was heated to 100° C. and stirred for five hours and allowed to cool to ambient temperature, poured onto water and then extracted with DCM. The extract was washed with brine, water, and dried. Volatile material was removed by evaporation to give the title compound (4.59 g) as an oil. NMR (CDCl3) 2.58 (m, 4H), 3.52 (m, 4H), 3.57 (s, 2H), 7.24-7.38 (m, 5H and CDCl3); m/z 326.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:11]=[C:12]([CH2:23][OH:24])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:11]=[C:12]([CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCc1c(COS(C)(=O)=O)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) and triethylamine (65.9 mg) in dichloromethane (2 mL) was added methanesulfonyl chloride (54.7 mg) under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL). The mixrure was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (5 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as an yellow gum (247 mg).
Reaction SMILES: O1CCCC1.B.CS(O)(=O)=O.[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH:14]=[C:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25].N>O>[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][CH:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: B
Agent: CS(=O)(=O)O
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask 1.0 M Borane tetrahydrofuran (37 mL) was taken. It was cooled to −10° C. and TEA (5.15 mL) was added dropwise at −10 to 5° C. After 30 min. methanesulfonic acid (6.0 mL) was added dropwise at −10 to 5° C. over a period of 15-30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added in small portions into the reaction mixture, keeping the temperature between −10 to −5° C. It was stirred for 1 h at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.2 g; % Y-83.6%; % Purity by HPLC-31%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].C(N(CC)CC)C>C(O)C.ClCCl>[CH3:18][C@@H:19]([CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[CH2:20][OH:21]
Reactant: C[C@H](CO)CBr
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](CO)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-trifluoromethyl-phenyl)-piperazine (52.0 g; 221 mmol); (R)-3-bromo-2-methyl-propan-1-ol (36.0 g; 226 mmol) and triethylamine (61.7 mL; 443 mmol) in ethanol (350 mL) is heated at 95° C. for 45 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure. The residue obtained is diluted with dichloromethane (500 mL) and the organic layer is washed with water (500 mL); with brine (500 mL) and the solvent is removed under reduced pressure. The crude residue obtained is re-crystallized from ethanol (200 mL), the re-crystallized product is washed with cold ethanol (100 mL). The mother liquor is concentrated under reduced pressure and is crystallized from ethanol (100 mL). The precipitate obtained is washed with cold ethanol (50 mL). The combined fractions are dried overnight at 40° C. under 3 mbar to deliver the enantiopure product (53.7 g; 178 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[C:34]1([NH:40][S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([S:41](=[O:43])(=[O:42])[NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Reactant: O=S(=O)(Cl)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(S(=O)(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry acetonitrile (5 mL) was treated with dry triethylamine (0.20 mL), then with phenylsulfamoyl chloride (100 mg Reference Example 44). After stirring at room temperature for a further 1 hour the reaction mixture was evaporated and the residue then treated with water and dichloromethane. The organic phase was separated, then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:1 v/v) to give 7-chloro-6-phenyl-2-phenylsulfamoyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (85 mg) as a white solid, m.p. 207–208° C. [Elemental analysis: C, 55.44; H, 4.34; N, 12.78%; Calculated for C20H19ClN4O3S: C, 55.75; H, 4.44; N, 13.00%].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].[OH:30][NH:31][C:32](=N)[CH3:33]>>[CH3:33][C:32]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][CH2:20][C:17]3[CH:18]=[N:19][C:14]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=5)[CH:8]=[CH:9]4)=[CH:15][CH:16]=3)[CH2:27][CH2:26]2)[O:30][N:31]=1
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(COC3CCN(C#N)CC3)cn2)c1
Reactant: CC(=N)NO
Product: Cc1noc(N2CCC(OCc3ccc(-n4ccc5cc(S(C)(=O)=O)ccc54)nc3)CC2)n1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-4 using 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)methoxy)piperidine-1-carbonitrile (intermediate 38) and N-hydroxyacetimidamide (0.014 g, 8%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:20]2[C:12](=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)[CH:11]([N:21]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:22]2[N:23]=[N:24][NH:25][N:26]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CO.[C:44]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH:1]([O:4][C:5]([N:7]1[C:20]2[C:12](=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)[CH:11]([N:21]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=2)[C:22]2[N:23]=[N:24][N:25]([CH3:44])[N:26]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)CCC3
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of (+/−)-isopropyl 9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (Example 49) (48 mg, 0.082 mmol) and methanol (0.015 mL, 0.36 mmol) in dichloromethane (1 mL) at room temperature, under nitrogen atmosphere, add triphenyl phosphine (22 mg, 0.082 mmol) in one portion. Add diethyl azodicarboxylate (0.015 mL, 0.082 mmol). The reaction mixture was allowed to stir at room temperature overnight. Add methanol (0.015 mL, 0.36 mmol), triphenyl phosphine (22 mg, 0.082 mmol) and diethyl azodicarboxylate (0.015 mL, 0.082 mmol). After stirring for 6 h, remove the solvents under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (25 mg, 51%). MS (ES+): 597 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[CH:13][C:14]=1[F:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CS(C)=O>[CH2:25]([O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Oc1cccc(F)c1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1Cl
Yield: 92.3 %

Procedure:
Treatment of 2′,4′-dichloro-6-fluorobiphenyl-2-ol (1.6 g, 6.2 mmol) with potassium carbonate (1.3 g, 9.3 mmol) and allyl bromide (0.79 mL, 9.3 mmol) in DMSO (50 mL) according to the procedure described for Example 69, Step 3 provided 1.7 g (92%) of 2′-allyloxy-2,4-dichloro-6′-fluorobiphenyl as a pale yellow oil.
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH:24]([CH3:26])[CH3:25])[N:5]([CH2:21][CH:22]=[CH2:23])[S:6]([N:9]([CH2:18][CH:19]=[CH2:20])[C@H:10]([C:14](OC)=O)[CH:11]([CH3:13])[CH3:12])(=[O:8])=[O:7].S(N[C@@H](C1C=CC=CC=1)C)(N[C@@H:32]([C:34]1C=CC=CC=1)[CH3:33])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:55](Br)[CH:56]=[CH2:57]>CC#N>[CH2:18]([N:9]([C@@H:10]([C:11]1[CH:13]=[CH:57][CH:56]=[CH:55][CH:12]=1)[CH3:14])[S:6]([N:5]([CH2:21][CH:22]=[CH2:23])[C@@H:4]([C:24]1[CH:26]=[CH:34][CH:32]=[CH:33][CH:25]=1)[CH3:3])(=[O:8])=[O:7])[CH:19]=[CH2:20]
Reactant: C=CCN([C@H](C(=O)OC)C(C)C)S(=O)(=O)N(CC=C)[C@H](C(=O)OC)C(C)C
Reactant: C[C@@H](NS(=O)(=O)N[C@H](C)c1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN([C@H](C)c1ccccc1)S(=O)(=O)N(CC=C)[C@H](C)c1ccccc1
Yield: 99 %

Procedure:
In a procedure similar to that used for the preparation of allylated sulfamide (9b), sulfamide (8e) (250 mg, 0.821 mmol) was subjected standard allylation procedures (K2CO3, allyl bromide, CH3CN 70° C., 24 hours). Flash chromatography (SiO2, Hexanes/EtOAc) yielded 313 mg (99%) of sulfamide (9e) as a clear oil. TLC Rf=0.59 (10:1 Hexanes/EtOAc); [α]25D=+77.5 (c=1.00, CHCl3); 1H NMR (CDCl3, 400 MHz) 7.46 (d, J=7.4 Hz, 4H), 7.39-7.35 (m, 4H), 7.32-7.30 (m, 2H), 5.79 (dddd, J=15.7, 9.7, 7.1, 5.8 Hz, 2H), 5.19 (q, J=7.1 Hz, 2H), 5.03 (dd, J=6.1, 1.3 Hz, 2H), 5.01-4.99 (m, 2H), 3.77 (dd with small allylic coupling, J=16.3, 5.8 Hz, 2H), 3.55 (dd, J=16.3, 7.2 Hz, 2H), 1.67 (d, J=7.1 Hz, 6H); 13C NMR (CDCl3, 100 MHz) 140.1, 135.9, 128.2, 127.9, 127.5, 116.9, 56.5, 47.3, 17.9; FTIR(neat) 3064, 3030, 2980, 2937, 1640, 1603, 1496, 1452, 1378, 1323, 1161, 784, 699 cm−1; HRMS (M+H)+ calculated for C22H29N2O2S 385.1950, found 385.1958.
Reaction SMILES: [Mg:1].C([Br:4])C.[CH3:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:7][CH3:8]>O1CCCC1>[CH3:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([Mg:1][Br:4])=[CH:20][CH:21]=1)[CH2:7][CH3:8]
Reactant: [Mg]
Reactant: CCN(C)CCCCCCOc1ccc(Br)cc1
Reactant: CCBr
Solvent: C1CCOC1
Product: CCN(C)CCCCCCOc1ccc([Mg]Br)cc1
Temperature: 5 °C

Procedure:
A 200 mL flask provided with a stirrer and a reflux condenser was charged in a nitrogen gas atmosphere with 1.2 g (0.05 mol) of metallic magnesium (cut form, 20-50 mesh size) (available from Yamaishi Metals Co., Ltd.), 20.0 g of tetrahydrofuran (available from Kanto Chemical Co., Inc.) and 0.3 g (0.003 mol) of ethyl bromide (available from Kanto Chemical Co., Inc.). The content was heated under reflux of solvent for 30 minutes. Then the reaction liquid was cooled to 5° C., and a solution in 30.0 g of tetrahydrofuran of 15.7 g (0.05 mol) of the p-(N-methyl-N-ethylaminohexyloxy)bromobenzene, synthesized at the above-mentioned step 2), was dropwise added at 5° C. over a period of 1 hour. The mixed reaction liquid was maintained at that temperature for 2 hours while being stirred. Thus a solution in tetrahydrofuran of the target p-(N-methyl-N-ethylaminohexyloxy)phenylmagnesium bromide was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+]>C(O)CO.C(OCC)(=O)C>[CH3:1][C:2]([CH3:28])([CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CC(C)(COC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Yield: 14.6 %

Procedure:
A solution of 53.5 g of raw methyl 2,2-dimethyl-3-trityloxy-propionate and 16.8 g of potassium hydroxide in 100 ml of ethylene glycol was heated to 160° C. for 4 hours. The mixture was cooled, diluted with 400 ml of ethyl acetate, and then washed successively with ice-cold 1N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was triturated with diethylether, unsoluble material was filtered off, and the filtrate was evaporated. Crystallization of the residue from diethylether/hexane provided 7.5 g of 2,2-dimethyl-3-trityloxy-propanoic acid, m.p. 153°-158° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]1.[OH-].[Na+].C(O)C>[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)N1CCN(CCCCCO)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Ethyl 4-(5-hydroxypentyl)piperazinecarboxylate (10.87 g, 65.09 mmol), 10% aqueous sodium hydroxide solution (150 mL) and ethanol (150 mL) were placed in a 500 mL round-bottomed flask, and heated under reflux with stirring overnight; the reaction system was cooled down to room temperature, and the solvent was distilled off under reduced pressure, to obtain a pale yellow oil; to the oil, 200 ml of saturated brine was added, followed by extraction with dichloromethane (5×200 mL); the resulting extract was dried with Na2SO4, filtered, and concentrated to obtain a pale yellow oil 9.69 g, yield 86.5% (which was directly used in the next step reaction).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 108 %

Procedure:
40 g (205 mmol, 1 equiv.) tert-butyl bromoacetate were dissolved in 200 ml acetonitrile. The solution was cooled to 0-5° C. and 47 g benzylamine (2.14 equiv.) in solution in 90 ml acetonitrile were added over 15 min. After 5 min, the reaction mixture was warmed to room temperature and stirred for 3 h (IPC by GC). The resulting suspension was filtered and evaporated to constant weight to give 49 g of a yellow oil. The oil was dissolved in 200 ml heptane and washed 3 times with 50 ml aq. sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated to give 35.8 g of the crude product. Distillation under high vacuum afforded 27.2 g of the title product (95% pure by GC).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:11])=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.C(O)(=O)C>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:9][C:5]3[C:6]([CH:22]=2)=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=3[F:11])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc3ccc(Cl)c(F)c3[nH]2)cc1
Temperature: 105 °C

Procedure:
(3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride (Apollo Scientific, Ltd., 221 mg, 1.12 mmol) and 4-acetyl-benzoic acid methyl ester (200 mg, 1.12 mmol) are treated with anhydrous ZnCl2 (382 mg, 2.81 mmol) and acetic acid (10 mL). The reaction is heated to 105° C. for 48 hours. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with H2O (5×) followed by saturated aqueous NaCl. The organics are then dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester as an off-white solid: ESMS m/z 304.0 (M+H+).