Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13](I)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.[Li+].[OH-]>C1COCC1.O>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([B:29]([OH:34])[OH:30])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1Oc1ncccc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a solution of 141a (3.35 g, 9.49 mmol) in THF (60 ml) under nitrogen at −78° C. was added 2.0 M nBuLi in pentane (14.2 mL, 28.47 mmol, 3 eq) over ˜3 min. The reaction was stirred at −78° C. for 10 min & then B(OiPr)3 (6.54 mL, 28.47 mmol, 3 eq) was added in a single aliquot. The reaction was stirred at −78° C. for 40 min and then the reaction was poured into water (˜60 mL) followed by the addition of LiOH (˜3.5 g). The reaction was stirred for 2 h at rt. Partition the reaction mixture between water (˜200 mL additional) and EtOAc (˜200 mL). Separate layers and wash the aqueous once more with EtOAc. Pour aqueous into a large erlenmyer flask & add EtOAc (˜200 mL). With vigorous stirring add conc. HCl dropwise until pH ˜2. Separate layers in sep. funnel & extract aqueous once more with EtOAc (˜200 mL). Combine these last two EtOAc extracts, dry over sodium sulfate, filter and concentrate. Azeotrope twice with toluene to give 234b (2.38 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (s, 9H); 4.1 (bs, 1H); 5.61 (bs, 1H); 6.91 (d, J=7.47 Hz, 1H); 7.05 (dd, J=6.37, 3.74 Hz, 1H); 7.15-7.3 (m, 2H); 7.48 (dd J=7.47, 1.32 Hz, 1H); 8.23 (bs, 1H); 8.27 (dd, J=7.03 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Li+].[OH-]>CO.O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncccc1OCC(F)(F)F
Reaction time: 2 h

Procedure:
A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg) in MeOH (1 ml) was treated with a solution of LiOH (78 mg) in water (0.1 ml) and stirring was continued at 22° C. for 2 h. The solution was evaporated and the residue triturated with 1N aqueous HCl. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. MS (ISP): m/z=220.0 [M−H]−.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>>[CH3:8][C:7]([CH3:10])([CH3:9])[CH2:6][O:11][CH2:4][CH:3]([OH:5])[CH2:1][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: ClCC1CO1
Reactant: CC(C)(C)CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)COCC(O)CN1CCCC1
Temperature: 95 °C
Yield: 84.1 %

Procedure:
To a stirred mixture of 92.53 g (1.0 m) of epichlorohydrin and 88.15 g (1.0 m) of neopentyl alcohol was added 0.26 g (0.001 m) of stannic chloride. The reaction temperature rose to about 60° C. then exothermed to about 130° C. in a few seconds. The reaction mixture was stirred until the temperature receded to about 40° C. then 71.12 g (1.0 m) of pyrrolidine was added. The reaction mixture was stirred and heated to about 95° C. for 1 hr. After cooling the reaction mixture to RT, a mixture of 80 g of 50% sodium hydroxide solution and 80 g of ice was added. The reaction mixture was stirred and heated to 90° C. for 0.5 hr then cooled to RT. The reaction mixture was partitioned between 400 ml of ice water and 400 ml of ether. The organic layer was dried and concentrated in vacuo to give 181 g of oil. The oil was distilled (89°-115° C. at 0.25 mm) to give 136 g of oil that crystallized on standing, 99.1% pure by g.c.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH3:29]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:18])[N:14]=1)=[O:37])[CH3:29]
Reactant: CCOC(=O)CCCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72), (0.1 g, 0.31 mmol) DIPEA (0.039 ml, 0.34 mmol), ethyl-4-isocyanatobutyrate (0.046 ml, 0.31 mmol) in DCM (2 ml) are heated together at reflux overnight. The reaction mixture is diluted with DCM (20 ml) and washed with 1M hydrochloric acid (15 ml), water (2×15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as an off white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1.CCCCCC>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25]
Reactant: Fc1ccc(CN2CCOCC2)cc1Br
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: -75 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
4-(3-Bromo-4-fluorobenzyl)morpholine (Preparation 7, 35.5 g) is dissolved in THF (400 mL) and cooled to −75° C. A solution of n-butyllithium in hexane (2.5 M, 57.0 mL) is added via addition funnel, maintaining the temperature below −68° C. A solution of N-methoxy-N-methylacetamide (16.0 g) in THF (50 mL) is added via addition funnel, maintaining the temperature below −65° C. The reaction is stirred at −75° C. for 1 h and allowed to warm to rt overnight. The reaction is quenched with 1 N HCl (150 mL) and poured into ethyl acetate (400 mL). The aqueous layer is separated, basified with sat. aq. NaHCO3, and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is distilled (135° C., 0.3 Torr) to afford 19.7 g (64%) of the title compound as a clear, colorless oil. Physical characteristics: Bp 135° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ7.72, 7.61-7.56, 7.31, 3.56, 3.48, 2.58, 2.34; IR (liq.) 1996, 1979, 1919, 1688, 1612, 1492, 1417, 1361, 1291, 1281, 1212, 1118, 865 cm−1; MS (ESI+) m/z 238 (M+H)+. Anal. Calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.43; H, 6.75; N, 5.84.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][OH:14].C(N(CC)CC)C.[CH3:22][O:23][C:24]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:25].OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:14][N:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:24]([O:23][CH3:22])=[O:25]
Reactant: COC(=O)CCCC(=O)O
Reactant: ONc1ccc2ccccc2c1O
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCC(=O)N(O)c1ccc2ccccc2c1O
Temperature: 0 °C
Yield: 56 %

Procedure:
Into a solution of 2 g (9.5 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride in THF (10 ml) and water (2 ml) was added 2 ml (14.2 mmol) of triethylamine, the mixture was cooled to 0° C., and 395 mg (2.4 mmol) of acid chloride of 4-methoxycarbonylbutanoic acid was added followed by stirring at room temperature. Aqueous KHSO4 was then added and the mixture extracted with CH2Cl2. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under a reduced pressure, and the residue subjected to silica gel column chromatography to give 405 mg (56%) of a hydroxyamic acid derivative.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.Br[C:17]1[CH:18]=[C:19]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.[Pd].C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][P:4]([O:5][CH2:6][CH3:7])([C:21]1[CH:20]=[C:19]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17][CH:22]=1)=[O:8])[CH3:2]
Reactant: COC(=O)CNCc1cccc(Br)c1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1cccc(CNCC(=O)OC)c1
Temperature: 25 °C

Procedure:
A solution of diethylphosphite (1 ml, 6.75 mmol) and triethylamine (5 ml) is stirred under a nitrogen atmosphere and then treated with tetrakis (triphenylphosphine) palladium (0) (0.4 g). A solution of methyl N-[(3-bromophenyl)methyl]glycinate (Example C) (1.62 g, 6.28 mmol) in toluene (10 ml) is degassed in vacuo, added to the palladium catalyst mixture, and the reaction vessel immersed in a 105° C. oil bath for 17 hours. The reaction mixture is cooled to room temperature and diluted with diethyl ether. An insoluble precipitate is removed by filtration and the filtrate evaporated to give a yellow residue. The product is purified by chromatography on silica gel (0-5% methanol in chloroform as eluant). 1H-NMR: 4H, m, 7.9-7.3 ppm; 4H, m, 4.25-3.95; 2H, s, 3.8; 3H, s, 3.7; 2H, s, 3.4; 6H, t, 1.25.
Reaction SMILES: COC(CCC/C=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=O.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C(O)(=O)C.O>O1CCCC1>[OH:17][CH:10]1[CH2:9][CH2:16][CH:15]2[CH:11]1[CH2:12][CH2:13][CH2:14]2
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: OC1CCC2CCCC12
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A stirred solution of 6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (6.7 mg), prepared as described in Example 8 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate, in tetrahydrofuran (0.5 ml) at -78° C. was treated dropwise with a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (0.0196 ml; 1.0M). The stirred solution was allowed to warm to 0° during 2 hours and then it was stirred for a further period of 2 hours. Glacial acetic acid (0.15 ml) and water (0.2 ml) were then added to the mixture, which was then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with aqueous sodium bicarbonate solution (2M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting oil was treated with a solution of sodium hydroxide in 50% v/v aqueous methanol (0.1 ml; 2.5N) and stirred for 150 minutes at 20° C. The mixture was then carefully concentrated in vacuo, and diluted with water (6 ml) and diethyl ether (3 ml). The aqueous phase was separated, acidified to pH 3 by treatment with hydrochloric acid (2N), and extracted with ethyl acetate (4×10 ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The resulting residue was subjected to chromatography on a silica gel column, using a mixture of ethyl acetate, hexane and glacial acetic acid (50:50:1 by volume) as eluant, to give 3-[(E)-4-carboxybutylidene]-6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]-2-hydroxybicyclo[3,3,0]octane (3.6 mg), predominantly in the 6β,6α-configuration, otherwise known as (±)-(5E,13E)-(6aS,9S),[mixture of (15R) and (15S)]-6a,15-dihydroxy-6,9-methano-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid [NMR in deuterochloroform: multiplets at 5.5, 3.5, 2.7-0.7 p.p.m⟧
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:43]NC1CCCC1>CS(C)=O.C1COCC1>[CH:1]1([N:6]([CH3:43])[C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC1CCCC1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1)C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.033 mmol), prepared as described in Procedure 3, 4, 5, 6 and 2, in DMSO/THF (0.1 mL/0.1 mL) was added N-methylcyclopentanamine (32 mg, 0.33 mmol). The resulting solution was stirred at 120° C. under microwave irradiation for 1800 sec. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was then washed with H2O, sat. NaCl and dried over Na2SO4. The organic solvent was evaporated under reduced pressure and the resulting residue was purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-1-methylurea (Example 246) as white lyophillate (13 mg, 65% yield). LCMS: [M+H] 619.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[C:12]([NH:19][C@H:20]([C:28]([OH:30])=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:28](=[O:30])[C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of dimethylamine hydrochloride (1.45 g, 17.8 mmol) in DMF (46 mL) was cooled to −10° C and triethylamine (2.7 mL, 19.4 mmol) was added. N-Boc-L-phenylalanine (4.59 g, 17.3 mmol, Aldrich) and HOBt (3.49 g, 26 mmol) were then added and the reaction stirred for 5 min before addition of EDCI (3.33 g, 17.4 mmol). The reaction mixture was left to stir for 16 h then diluted with ethyl acetate (400 mL), washed sequentially with aqueous sodium hydroxide solution (2M, 2×100 mL), hydrochloric acid (2N, 2×100 mL), brine (250 mL) and then dried (MgSO4). Evaporation in vacuo gave the title compound as a pale yellow oil. δH (CDCl3): 1.41 (9H, s), 2.61, 2.85 (6H, 2s), 2.91-2.99 (2H, m), 4.83 (1H, m), 5.40 (1H, br d), 7.18-7.29 (5H, m).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCCC1.CCOCC>[CH2:24]([O:23][C:21]([NH:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][NH:4][C:3]1=[O:13])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
A solution of 210 mg (1.19 mmol) of 4(R)-amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one in 5 mL of tetrahydrofuran was treated with 5 mL of 10% aqueous potassium carbonate followed by 0.20 mL (0.24 g, 1.3 mmol, 1.1 eq) of 95% benzyl chloroformate. The mixture was stirred vigorously at room temperature for 6 hours then diluted with 20 mL of ether and the mixture transferred to a separatory funnel. The lower aqueous layer was removed and washed with several portions of ether. The combined ether washes and ether layer were washed, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and solvents removed under vacuum to give 365 mg (1.14 mmol, 96%) of the product. 1H NMR (400 MHz, CDCl3): δ3.08 (dd; 12, 16 Hz; 1H), 3.27 (dd; 7, 16 Hz; 1H), 4.06 (d, 16 Hz, 1H), 4.75 (d, 16 Hz, 1H), 5.00 (dd; 7, 12 Hz; 1H), 5.12 (s, 2H), 7.1-7.4 (m, 9H).
Reaction SMILES: [N:1]1([S:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:9]([S:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:7])=[O:8])[C:10](=[O:12])[CH3:11])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(=O)CS(=O)(=O)N1CCCC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)S(=O)(=O)N1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Alternatively, the Bignelli reaction was carried out in two steps with higher yields. To 1-(pyrrolidin-1-ylsulfonyl)propan-2-one in THF was added an equivalent amount of 3,4-dichlorobenzaldehyde and a catalytic amount of titanium tetraisopropoxide. The reaction was stirred at 80° C. overnight. Solvent was removed and the residue was purified by silica flash chromatography (0% to 15% ethyl acetate-hexanes) to provide 4-(3,4-dichlorophenyl)-3-(pyrrolidin-1-ylsulfonyl)but-3-en-2-one. The product obtained was dissolved in 1,4-dioxane and one equivalent of 3-methyl-1H-pyrazol-5-amine was added. The reaction was stirred at 80° C. for 24-48 hrs. Solvent was removed and product was obtained after flash chromatography (silica gel, 0% to 40% ethyl acetate-hexanes).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:35][C:34]1[C:26]([F:25])=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:36])=[CH:28]2)#[N:13]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: CN1CCN(CCCOc2cc3nccc(Cl)c3cc2C#N)CC1
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ccnc4cc(OCCCN5CCN(C)CC5)c(C#N)cc34)ccc2[nH]1
Yield: 44.3 %

Procedure:
Using an analogous procedure to that described in Example 11, 4-chloro-6-cyano-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (500 mg, 1.45 mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (287 mg, 1.74 mmol), (prepared as described for the starting material in Example 11), in DMF (1 ml) to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (304 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:11]([Mg]Cl)[CH3:12].C([N:22]1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1.CC1C=CC=C(C)C=1CN1C2C(=CC=C(C(O)=O)C=2)C=C1>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:22][N:9]=[C:8]([CH2:11][CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: CC[Mg]Cl
Reactant: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Reactant: N#Cc1ncc(Br)cc1F
Agent: Cc1cccc(C)c1Cn1ccc2ccc(C(=O)O)cc21
Product: CCc1n[nH]c2cc(Br)cnc12

Procedure:
The titled compound (225 mg) as a white solid was prepared from 5-bromo-3-fluoropyridin-2-carbonitrile (201 mg) obtained by the method described in the document (Journal of Organic Chemistry, 2009, Vol. 74, p. 4547) and ethylmagnesium chloride according to the methods of the processes (1) and (2) of Example 153.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[OH:14][CH2:15][C:16]1[S:17][S:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=1.S1C=CC=CS1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CCOCC>[CH:8]1([C:11]([O:14][CH2:15][C:16]2[S:17][S:18][C:19]([CH2:22][O:23][C:34]([CH:33]3[CH2:31][CH2:32]3)=[O:30])=[CH:20][CH:21]=2)=[O:12])[CH2:10][CH2:9]1
Reactant: O=C(Cl)C1CC1
Reactant: OCC1=CC=C(CO)SS1
Reactant: C1CCOC1
Agent: C1=CSSC=C1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCC1=CC=C(COC(=O)C2CC2)SS1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of triethylamine (0.30 mL) in tetrahydrofuran (2.0 mL) at 0° C. was added dropwise cyclopropanecarbonyl chloride (0.10 mL) followed by the addition of 3,6-bis(hydroxymethyl)-1,2-dithiin, Dithiin A (20 mg, 0.113 mmol) in tetrahydrofuran (1.0 mL). After stirring in the dark at room temperature overnight the mixture was diluted with ether (20 mL) and partitioned between 1.0M H3PO4 (80 mL) and diethyl ether (30 mL). The diethyl ether layer was washed with saturated NaHCO3 (100 mL), dried (Na2SO4), and evaporated to give a red oil (31.5 mg): 1H NMR (CDCl3) δ6.38 (s, 2H), 4.71 (s, 4H), 1.67 (m, 2H), 1.04 (m, 4H), 0.92 (m, 4H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C:8]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccccc2)CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of methanesulphonyl chloride (1.62 g) in dry dichloromethane (10 ml) was added over 20 minutes to a stirred mixture of 1-hydroxymethyl-1-phenylcyclopentane (1.91 g) and triethylamine (1.64 g) in dry dichloromethane (50 ml) at 0° C. (white precipitate). After 1 hour, all at about 0° C., water was added to the reaction mixture and the organic and aqueous layers were separated. The organic layer was washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, then dried over magnesium sulphate and concentrated to give almost pure 1-methanesulphonyloxymethyl-1-phenylcyclopentane (2.85 g) as an almost colourless oil which crystallised completely on standing in the fridge, melting point 55°-60° C., 1H n.m.r. (CDCl3): δ 2.51 (3H, s, CH3SO2), 4.16 (2H, s, CH2OSO2CH3).