Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[O:5][CH2:4]1.[NH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:7]1([N:6]2[CH2:4][CH:3]([OH:5])[CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: ClCC1CO1
Reactant: NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: OC1CN(C2CCCC2)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 1-chloro-2,3-epoxypropane (784 μL, 10 mmol) and amino cyclopentane (988 μL, 10 mmol) in dry acetonitrile (10 ml), sodium bicarbonate (1.68 g, 20 mmol) was added, and the resulting mixture was heated to reflux until the completion of reaction (TLC, 5h). The reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentrated in vacuo to afford an oily residue, which was purified by flash chromatography (silica gel, EtOAC/MeOH, 9:1) to furnish the title compound (565 mg, 40%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 4.40-4.32 (m, 1H), 3.58-3-53 (m, 2H), 2.90-2.84 (m, 2H), 2.72-2.65 (m, 1H), 1.70-1.23 (m, 8H), ESIMS m/z [M+H]+ 142.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:31][N:21]([CH3:20])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)=[CH:26][CH:25]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: CN(C)CCc1ccc(O)cc1
Product: CN(C)CCc1ccc(OCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-(2-dimethylaminoethyl)-phenol. 1H NMR (400 MHz; CDCl3): δ 2.85 (s, 6H), 2.98-3.02 (m, 2H), 3.17-3.21 (m, 2H), 3.42 (br s, 3H), 5.02 (s, 2H), 6.90 (d, 2H), 7.12 (d, 2H), 7.25-7.43 (m, 7H); HPLC-MS: m/z=405.2 (M+1); Rt=2.91 min.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:14][O:15][C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[C:18]([O:24][CH3:25])[N:17]=1.[Cl-].[NH4+]>C1COCC1>[CH3:14][O:15][C:16]1[C:21]([CH:22]([OH:23])[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:19]=[C:18]([O:24][CH3:25])[N:17]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(C=O)c(OC)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of phenylacetylene (0.61 g, 5.98 mmol) in dry THF (10 mL), cooled to −78° C., was added 2.5 M nBuLi in hexanes (2.4 mL, 6.0 mmol). The mixture was stirred for 15 min at −78° C., followed by addition of a solution of 2,6-dimethoxypyridine-3-carbaldehyde (1.0 g, 6.0 mmol) in THF (10 mL) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C. and saturated ammonium chloride was added. The resultant biphasic mixture was separated and extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 30% ethyl acetate in cyclohexane) to afford the title compound (1.60 g, 99%) as a colourless gum. LCMS (Method B): RT=4.38 min, [M+H]+=270.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:33])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:34](N(CC)CC)[CH3:35].ICC>CN(C)C=O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:33])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C4CCNCC4)[nH]c3-c3ccccc3)cc21
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCC(c2nc(-c3ccc4nc(N)n(S(=O)(=O)C(C)C)c4c3)c(-c3ccccc3)[nH]2)CC1
Yield: 76 %

Procedure:
Stir a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(piperidin-4-yl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.574 g, 1.23 mmol), triethylamine (3.1 mmol), and iodoethane (1.54 mmol) in anhydrous dimethylformamide (5 mL) at room temperature for 6 hours. Partition the mixture between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (3 times). Wash the combined organic layers sequentially with cold water (5 times) and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography to provide the title compound in 76% yield. MS(ES+): m/z=493.2 (M+H)+
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:33])[CH2:6][NH:7][C:8]([C:10]1[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]#[N:20])=[CH:14][CH:13]=2)=[O:9])C.[BH4-].[Li+]>O1CCCC1.O>[OH:3][CH2:4][CH:5]([CH3:33])[CH2:6][NH:7][C:8]([C:10]1[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]#[N:20])=[CH:14][CH:13]=2)=[O:9]
Reactant: CCOC(=O)C(C)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
3-{[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methylpropionic acid ethyl ester (170 mg, 0.36 mmol) was dissolved in dry tetrahydrofuran (10 ml) and lithium borohydride (28 mg, 1.28 mmol) was added and heated to reflux for 90 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×30 ml), the organic layers were combined and washed with water (20 ml) and saturated sodium chloride solution (20 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (3-hydroxy-2-methylpropyl)amide as a pale yellow solid which was purified by preparative HPLC (75 mg, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=O)[CH2:31]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>>[CH2:16]([C:15]1[C:30]([C:29]2[CH:34]=[CH:35][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)=[CH:31][N:11]2[C:10]=1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:14][CH:13]=[CH:12]2)[CH3:17]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: CCCc1ncccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(OCc3ccccc3)c12
Yield: 66 %

Procedure:
3-Benzyloxy-2-propylpyridine was reacted with 4-benzyloxyphenacylbromide and with sodium hydrogen carbonate by the general synthetic principles outlined in example 1, step 2, to afford 1-ethyl-8-benzyloxy-2-(4-benzyloxyphenyl)indolizine as yellow crystals in 66% yield. M.p. 104-105° C. MS(SP): m/z 433 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, 3 H); 2.86 (q, 2 H); 5.12 (s, 2 H); 5.19 (s, 2 H); 6.13 (d, 1 H); 6.38 (t, 1 H); 7.06 (d, 2 H); 7.28-7.54 (m, 13 H); 7.77 (d, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N+:9]=1[O-:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(N)c(C(=O)OC(C)(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
20.37 g (92.2 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine was dissolved in 100 mL of chloroform, and the resulting solution was cooled with ice water. 25 g (101.4 mmol) of a 70% by weight product of meta-chloroperbenzoic acid was added thereto. After confirming that there is no large heat generation, the temperature was raised to room temperature. After 2 hours had elapsed, 20 mL of water was added thereto. Then, the pH was adjusted to 14 by adding an aqueous solution of caustic soda having a concentration of 28%. Following liquid separation, the resulting aqueous layer was extracted with chloroform. The chloroform layer was washed with a 28% aqueous solution of caustic soda and then with water, and then dried with magnesium sulfate. Chloroform was removed by distillation under reduced pressure to obtain 21.30 g of 2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide (yield: 99.6%) in a light orange oily form.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(C(C)C)CC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:5]1[N:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[N:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Brc1cnc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(Br)cn1
Temperature: 115 °C
Yield: 8.6 %

Procedure:
A solution of 2,5-dibromopyrazine (238.0 mg, 1.0 mmol), ethyl acrylate (174.0 μL, 1.6 mmol), palladium(II) acetate (3.4 mg, 0.015 mmol), and tri(o-tolyl)phosphine (36.5 mg, 0.12 mmol) in DMF (1.4 mL) and diisopropylethylamine (0.7 mL) was heated at reflux (115° C. oil bath) for 4.4 h, cooled to room temperature, and then quenched with H2O. The suspension was extracted with EtOAc (300 mL). The extract was washed (brine) and dried. After solvent removal at reduced pressure, the residue was purified on silica gel (11% EtOAc/hexane) to give 22 mg (8.5%) of ethyl(E)-3-(5-bromo-2-pyrazinyl)-2-propenoate as a cream solid.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: COc1cccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)c1
Temperature: 25 °C

Procedure:
21.28 g (84.7 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 17.4 g (84.7 mmol) of 3-dimethylamino-1-(3-methoxy-phenyl)-2-propen-1-one in 100 ml of 2-propanol. After the addition of 3.72 g (93.2 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 21.3 h. After cooling to RT, the product is isolated by filtration and washed with 1-propanol and water. After drying at 60° under HV, N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-methoxy-phenyl)-2-pyrimidineamine is obtained; Rf =0.7 (methylene chloride:methanol =9:1), FAB-MS: 397 (M+ +1), m.p. 103°-104°.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:16][CH2:15][C:11]2[CH:10]=[CH:9][C:8]3[CH2:7][CH2:6][C@@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])[CH2:14][C:13]=3[CH:12]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(CN)cc2C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCCN(CCC)[C@@H]1CCc2ccc(CNS(=O)(=O)c3ccc(Cl)cc3)cc2C1

Procedure:
Using procedure 9, (R)-7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenemethanamine (9) was treated with 4-chlorobenzenesulfonyl chloride. Purification by chromatography gave a solid which was crystallized from hexane to give the title compound colorless crystals (m.p. 72° C.). [α]D =+47° (25° C., CH3OH, c=0.6095).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C@@H:8]([CH2:15][C:16]([O:18]C)=[O:17])[N:7]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=3)[C:6]=2[N:5]=1>CO.C1COCC1>[NH2:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C@@H:8]([CH2:15][C:16]([OH:18])=[O:17])[N:7]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=3)[C:6]=2[N:5]=1
Reactant: COC(=O)C[C@@H]1C(=O)Nc2cnc(N)nc2N1Cc1ncc(C)c(OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@H]2CC(=O)O)c1C
Reaction time: 2 h

Procedure:
Sodium hydroxide (1 mL, 2M, 2 mmol) was added to a solution of methyl {(7R)-2-amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-6-oxo-5,6,7,8-tetrahydropteridin-7-yl}acetate (272 mg, 0.26 mmol)(Example 7[3]) in methanol (1 mL) and THF (3 mL). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The solution was diluted with water (1 mL) and made acidic by the addition of acetic acid. This solution was loaded onto an SCX column, washed with water and then methanol and the product was eluted with 2M ammonia in methanol. Thus, the title compound was obtained as a cream solid (169 mg, 65%); 1H NMR spectrum (400 MHz, DMSO-d6) δ 2.18 (6H, s), 2.29 (1H, d), 2.38 (1H, d), 3.72 (3H, s), 4.13-4.15 (1H, m), 4.41 (1H, d), 5.49 (1H, d), 5.55 (2H, s), 7.27 (1H, s), 8.13 (1H, s), 9.91 (1H, s); Mass spectrum: (M+H)+ 373.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.CCCCCC.[F:20][CH2:21][C:22](OCC)=[O:23]>C1COCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:22](=[O:23])[CH2:21][F:20]
Reactant: CCOC(=O)CF
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CF)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a cooled (−78° C.) solution of 1,2-difluorobenzene (8.81 mL, 89 mmol) in THF (175 mL) was added dropwise butyllithium solution, 1.6M in hexane (61.5 mL, 98 mmol). After stirred for 2 h, ethyl fluoroacetate (8.64 mL, 89 mmol) ethyl fluoroacetate was added dropwise. The reaction was stirred for 1 h, the reaction was quenched with saturated NH4Cl and then warmed to room temperature. The resulted mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-30% EtOAc/hexane) to afford 6.3 g of desired product as colorless oil.
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Br-].[NH4+].O1C[CH2:13][CH2:12][CH2:11]1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:7][CH:1]([C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: C1CCOC1
Reactant: O=Cc1ccco1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=CCC(O)c1ccco1

Procedure:
Reaction and after-treatment were carried out in the same manner as in Example 3 except that an equimolar amount of furfural was used in place of 5-methylfurfural, and that ammonium bromide and tetrahydrofuran were used in place of ammonium chloride and toluene, respectively, in the same weights as those of the latter, to obtain 50.6 g of the fraction of 2-(1-hydroxy-3-butenyl)-furan (content, 99.3%) (yield, 91.0%).
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19]C)[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[BrH:21]>>[BrH:21].[OH:19][C:12]1[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: Br
Product: CS(=O)(=O)c1cc2c(cc1O)CCNCC2

Procedure:
3-Acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1 g, 0.003 m), prepared as in Method A or B, in 48% hydrobromic acid (15 ml) was heated to reflux for 16 hours and concentrated in vacuo. The residue was triturated with acetone and recrystallized from methanol-water to give 8-hydroxy-7-methylsulfonyl-2.3.4.5 -tetrahydro-1H-3-benzazepine hydrobromide, m.p. 300° (decomp.).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:2][CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: BrP(Br)Br
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CBr
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.2 %

Procedure:
To a solution of phosphorus tribromide (0.93 g) in tetrahydrofuran (10 ml) was dropwise added a suspension of 3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (1.65 g) in tetrahydrofuran (10 ml) at 5°-10° C. After stirring for 1.5 hours at the same temperature, the reaction mixture was poured into ice-water (20 ml), adjusted to pH 9.5 with saturated aqueous potassium carbonate and extracted with ethyl acetate (40 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with chloroform. The fractions containing the desired compound were combined and evaporated in vacuo to give 3-bromomethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.49 g).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2[CH:19]=O)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Li+].[S:29]1[CH:33]([C:34](=[O:44])[CH2:35]P(=O)(OCC)OCC)[CH:32]=[C:31]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:30]12>C(Cl)Cl.C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2/[CH:19]=[CH:35]/[C:34]([C:33]2[S:29][C:30]3[CH:48]=[CH:47][CH:46]=[CH:45][C:31]=3[CH:32]=2)=[O:44])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CC(=O)C1C=C2C=CC=CC2S1)OCC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: -20 °C

Procedure:
A reactor equipped with a mechanical stirrer, under nitrogen, was charged with a mixture consisting of (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate in DCM and a mixture consisting of lithium chloride (1 molar equivalent) in THF. Diethyl 2-(2,7a-dihydrobenzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) was added neat and rinsed with DCM. Some lithium chloride precipitated from solution when the THF and DCM mixtures were combined. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and further stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) was added neat via addition funnel and the temperature was maintained at −5° C. for 19 hours. The temperature was adjusted to 0° C. and the reaction mixture was treated with 5% aqueous citric acid. The layers were separated and the organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 27; 1H NMR (CDCl3) δ 8.10-8.15 (m, 2H), 8.05 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.75 (m, 4H), 7.38-7.60 (m, 5H), 6.98-7.17 (m, 2H), 5.45-5.55 (m, 1H), 5.18-5.25 (m, 1H), 2.93-3.15 (m, 3H), 2.55-2.77 (m, 2H), 2.38-2.47 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN1CCN(Cc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cc2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCN(Cc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cc2)CC1
Yield: 83 %

Procedure:
Following general procedure D, {6-bromo-4-[4-((4-methylpiperazin-1-yl)methyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (42 mg, 0.088 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.132 mmol) to afford the desired product (41 mg, 83%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 7.93-7.85 (m, 2H), 7.74 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.19-7.10 (m, 4H), 3.61 (s, 2H), 2.95-2.88 (m, 1H), 2.74-2.68 (m, 4H), 2.57-2.46 (m, 7H), 1.23-1.10 (m, 4H); ESI MS m/z 561 [C31H30Cl2N4O2+H]+; HPLC 94.4% (AUC), tR=8.57 min.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][S:1]([O:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Reaction time: 0.33 h

Procedure:
Mesyl chloride (106 μL, 1.37 mmol) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (250 mg, 1.242 mmol) and triethylamine (225 μL, 1.62 mmol) in DCM at 0° C. After 20 min, the reaction mixture was diluted with DCM, washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-14a. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 3.20-3.60 (m, 3H), 3.17 (m, 1H), 3.05 (s, 3H), 2.65 (m, 1H), 2.07 (m, 1H), 1.74 (m, 1H), 1.48 (s, 9H).