Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]([CH:30]([F:41])[C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[C:28]([CH:42]4[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]4)[C:27]4[CH:26]([O:50]CC5C=CC(OC)=CC=5)[CH2:25][C:24]([CH3:61])([CH3:60])[CH2:23][C:22]=4[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1>>[F:49][C:45]1([F:48])[CH2:44][CH2:43][CH:42]([C:28]2[C:27]3[CH:26]([OH:50])[CH2:25][C:24]([CH3:60])([CH3:61])[CH2:23][C:22]=3[N:21]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:11]4[N:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]5)=[CH:9][N:10]=4)[CH2:19][CH2:18]3)[C:29]=2[CH:30]([F:41])[C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=2)[CH2:47][CH2:46]1
Reactant: O[C@H]1CCNC1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(N5CC[C@H](O)C5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 13 were performed except for using (3S)-3-pyrrolidinol instead of isonipecotic acid ethyl ester, and from 100 mg (0.120 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 56 mg of the title compound was obtained as a white solid (yield: 65%).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH:20]=[O:21])[C:10]=1[CH3:22])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:20]=[O:21])[C:10]([CH3:22])=[C:9]2[OH:8]
Reactant: Cc1c(C=O)cc2ccc(F)cc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C=O)cc2ccc(F)cc2c1O
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (165 mg, 0.56 mmol) in ethyl acetate (5 mL) was added 10% palladium on carbon (7 mg). The resulting mixture was stirred vigorously under a hydrogen atmosphere (balloon) for 4 hours, and then filtered. The filtrate was concentrated in vacuo to give 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carbaldehyde (115 mg, 99%) as a yellow solid which was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]CC(C1C=CC(O)=CC=1O)=O>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH2:10][CH3:13])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Product: CCC(=O)c1ccc(O)c(Cl)c1O

Procedure:
The title compound was prepared in a similar manner to 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (Preparation 3) employing 2,4-dihydroxypropiophenone to give 4.5 g, 37% of an off-white solid. LCMS 1 201 M+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N+:13]([O-:15])[CH3:14])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[O:15][N:13]([CH3:14])[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)([CH2:7][N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)[CH2:22]2)=[CH:19][CH:18]=1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccco1
Reactant: C=Cc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1OC(c2ccc(Cl)cc2)CC1(Cn1ccnc1)c1ccco1
Temperature: 25 °C

Procedure:
A solution of 7.60 g (0.037 mol) of 1-(2-furanyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (4) and 7.70 g (0.056 mol) of 4-chlorostyrene in 400 ml of toluene is refluxed for 48 hours under a nitrogen atmosphere. Upon cooling to ambient temperature, the crude cis- and trans-diastereomeric mixture of compound 6 (R=C6H4Cl--4) is concentrated in vacuo and flash-chromatographed on neutral silica gel using a 98:2 by volume mixture of chloroform and methanol to give 1.30 g (10%) of isomer A, melting point 99°-101° C. (ethyl acetate-hexane, 1:1 by volume). Anal. Calcd. for C18H18ClN3O2 : C, 62.88; H, 5.28; Cl, 10.31; N, 12.22 Found: C, 62.90; H, 5.39; Cl, 10.44; N, 12,13. Isomer B (1.10 g, 8.5%) has a melting point of 131°-133° C. (ethyl acetate-hexane, 1:1 by volume). Anal. Calcd. for C18H18ClN3O2 : C, 62.88; H, 5.28; Cl, 10.31; N, 12.22. Found: C, 62.82; H, 5.28; Cl, 10.46; N, 12.12.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([CH3:19])=[C:9]2[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:24]1)=[O:21])(=O)C.[OH-].[K+]>CO>[CH2:15]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([OH:5])=[CH:14][CH:13]=2)[C:9]([C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:28]2)=[O:21])=[C:10]1[CH3:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCn1c(C)c(C(=O)NC2CCN(CCc3ccccc3)CC2)c2cc(OC(C)=O)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1c(C)c(C(=O)NC2CCN(CCc3ccccc3)CC2)c2cc(O)ccc21

Procedure:
To a solution of 2.3 g of 5-acetoxy-1-butyl-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide hydrochloride in 30 ml of methanol was added a solution of 0.5 g of potassium hydroxide in methanol, and the whole solution was stirred for an hour under heating. After the reaction mixture was cooled, the precipitated inorganic substance was filtered off and the filtrate was concentrated under reduced pressure. A solution of the residue in water with a small amount of ethanol was stirred and the precipitated crystals were filtered with suction. Recrystallization from ethyl acetate gave 1-butyl-5-hydroxy-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide as white crystals, melting at 178°-181° C. The corresponding hydrochloride monohydrate melts at 244°-247° C. with decomposition.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26].O>O1CCCC1>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:3]1[CH2:4][CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7][C:2]1=[O:1]
Reactant: O=C1CC(C(=O)O)CCN1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 2-oxopiperidine-4-carboxylic acid (21.3 g) in tetrahydrofuran (300 mL) was added 60% sodium hydride (18 g, containing mineral oil) under cooling to 0° C. The reaction mixture was stirred for 30 min under cooling to 0° C. To the reaction mixture was added dropwise 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (46 g) under cooling to 0° C., and the mixture was further stirred at 80° C. for 2 days. Water was added to the reaction mixture under cooling to 0° C., and the mixture was extracted with ethyl acetate. To the aqueous layer was further added 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (32 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:22]=[CH:23]/[N+:24]([O-])=O)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:22][CH2:23][NH2:24])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1-c1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(OCc2ccccc2)cc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitrostyrene 28 (400 mg, 1.1 mmol) in freshly distilled THF (2 mL) was added dropwise to a solution of LiAlH4 (87 mg, 2.2 mmol), at 0° C. under an argon atmosphere. Upon completion of the reaction (from TLC) the reaction was quenched by addition of water (45 μL), 3M NaOH (45 μL), and an additional 80 μL water, and 20 mL EtOAc. The resulting mixture was stirred at room temperature for 1 h, filtered through a plug of celite, washed with EtOAc, dried (Na2SO4) and concentrated to a crude brown mixture, which was purified by column chromatography (Silica gel, 10% MeOH in DCM) to give the desired product.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:13][C:3]2[C:2]([F:1])=[CH:12][C:6]3[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=3[CH:4]=2)[CH:23]=1
Reactant: CSc1nc2cc(F)c(CNc3ncccc3N)cc2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CSc1nc2cc(F)c(Cn3cnc4cccnc43)cc2s1

Procedure:
6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-2-(methylthio)benzo[d]thiazole was synthesized as a tan solid (180 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N2-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][CH:16]=2)[CH2:11]1)(=[O:9])[CH3:8].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>ClCCCl>[N:24]1([S:20]([C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][CH2:19][N:10]([C:7](=[O:9])[CH3:8])[CH2:11]3)=[CH:16][CH:15]=2)(=[O:22])=[O:21])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCc4ccccc43)cc2C1
Reaction time: 3 h
Yield: 66.5 %

Procedure:
Pyridine (0.85 ml, 10.5 mmol) was added to a stirred solution of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (0.96 g, 3.5 mmol) and 2,3-dihydro-1H-indole (0.42 g, 3.5 mmol) in 1,2-dichlorethane (40 ml) at room temperature. After 3 h, the solution was washed with water (40 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by column chromatography over silica gel eluting with a gradient of dichloromethane/methanol to afford the title compound (D5) as an oil (0.83 g, 67%), MS: m/z (MH+) 357.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].[H-].[Na+].C(Cl)C1C=CC=CC=1>>[CH3:1][O:2][C@@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: ClCc1ccccc1
Product: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 115 °C
Yield: 148.1 %

Procedure:
A general procedure according to S. Koto et al. (Bull. Chem. Soc. Japan, (1976), 49:2939-40) was followed. A suspension of methyl-α-D-glucopyranoside (Aldrich, 5.02 g, 0.0259 mol), sodium hydride (Aldrich, 4.31 g, 0.1796 mol) and benzyl chloride (Aldrich, 125 ml, 25:1 (v/w) vs carbohydrate) was stirred vigorously and heated to a bath temperature of 115° C. whereupon the gray reaction mixture thickened and an exotherm occurred. The reaction mixture reached 135° C. and turned into a thin, yellowish slurry. The reaction was allowed to stir at this temperature for 1 h. The insoluble material was removed by filtration and the solution concentrated in vacuo. Flash chromatography on silica gel (E. M. Science, 230-400 mesh) using methylene chloride as eluant gave the product (Rf value: 0.63) as an oil (7.45 g, 52%). 1H NMR data (CDCl3): δ7.27 (m, 20H, aromatic H on benzyl group), 3.45 (s, 3H, --OCH3 ).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[O:11]=[C:12]1[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[N:1][CH:19]=[C:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=NCCCCC1
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)CCCCC2
Reaction time: 1 h
Yield: 80.5 %

Procedure:
67.2 g of 7-amino-3,4,5,6-tetrahydro-2H-azepine are dissolved in 600 ml. of ethanol and the solution is cooled to -10° C. and to the reaction mixture a solution of 127.8 g. of diethyl ethoxy-methylene-malonate in 600 ml. of ethanol is added dropwise under stirring within 1 hour. The reaction mixture is stirred for a further hour at a temperature of -10° C. to -5° C. whereafter it is boiled for 1 hour. Ethanol is distilled off at reduced pressure. The residual yellow oil containing an about 10:1 mixture of ethyl 4-oxo-4,6,7,8-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate and ethyl-2-oxo-2,6,7,8,9,10-hexadhydro-pyrimido[1,2-a]azepine-3-carboxylate is dissolved in 600 ml. of benzene and shaken out twice subsequently with 60 ml of water. The benzene soltuion is dried over anhydrous sodium sulphate and evaporated at reduced pressure. 114 g. (80.5%) ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate are obtained melting at 82°-84° C. after recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.C[O:26][C:27](=[O:50])[C@H:28]([C@@H:47]([CH3:49])O)[NH:29]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2([O:22][C@H:47]([CH3:49])[C@@H:28]([C:27]([OH:50])=[O:26])[NH2:29])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2cccc(C(F)(F)F)c2)c2ccccc2-c2ccccc21
Product: C[C@@H](OC1(c2cccc(C(F)(F)F)c2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(3-trifluoromethylphenyl)-9H-fluoren-9-ol (Example 3m) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[CH2:13][CH2:14][CH:15]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)=[O:20])[CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[Li+].[Cl-].[C:38]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:39]=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN(C=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.O>[CH:38]([C:7]1[C:12]2[CH2:13][CH2:14][CH:15]([C:19]([N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)=[O:20])[CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[CH2:39]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1C1CCN(C(=O)C2CCc3c(OS(=O)(=O)C(F)(F)F)cccc3C(=O)C2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cccc2c1CCC(C(=O)N1CCC(c3ccccc3C)CC1)CC2=O
Temperature: 100 °C
Yield: 58.1 %

Procedure:
510 mg (1 mmol) of (±)-1-trifluoromethanesulfonyloxy-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were dissolved in 4 mL of DMF under an argon atmosphere, then 72 mg (0.1 mmol) of dichlorobis(triphenylphosphine)palladium (II), 340 mg (8 mmol) of LiCl and 105 mg (0.4 mmol) of triphenylphosphine were added, followed by a solution of 0.3 mL (1.04 mmol) of tributyl(vinyl)tin in 0.5 mL of DMF. The reaction mixture was heated to 100° C. for 6 h, then it was poured into water and extracted with AcOEt. The organic layer was dried and the solvent was removed in vacuo. The crude reaction mixture was purified by flash chromatography, eluting with a mixture AcOEt/hexane 1:1, yielding 90 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][C@H:14]([CH3:18])[NH:13]1>C(#N)C>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1

Procedure:
1-Fluoro-4-nitrobenzene (10 g, 70.87 mmol) and (2R,6S)-2,6-dimethylpiperazine (17 g, 148.83 mmol) were heated in acetonitrile (25 ml) at 70° C. for 2 h. The solution was concentrated in vacuo, then the residue was partitioned between DCM and water+sat. sodium hydrogen carbonate. The organic extract was washed with water (4 times), brine, dried and concentrated to give the title compound as a yellow solid which was dried in vac oven overnight at 50° C. (16.13 g, 97%). NMR (400 MHz) 1.04 (d, 6H), 2.39 (m, 2H), 2.77 (m, 2H), 3.89 (dd, 2H), 7.02 (d, 2H), 8.03 (d, 2H); m/z 236.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:18][CH2:17][C:16]([C:24]([O:26]C)=[O:25])=[CH:15][C:14]=3[CH:28]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:18][CH2:17][C:16]([C:24]([OH:26])=[O:25])=[CH:15][C:14]=3[CH:28]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.14 g). To the solution was added 1N sodium hydroxide solution (3 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with evaporated to give 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.13 g) as pale yellow crystals.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:37])[C:9]1=[O:38])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:38])[N:10]([CH3:37])[C:11]=3[CH:17]=[C:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1cc(-c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (30 mg, 0.054 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (4.58 mg, 0.109 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4 (3H,5H)-dione (4 mg, 14.4% yield) as a white solid. 1H NMR (CDCl3) δ: 7.47 (t, J=8.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.26-7.24 (m, 1H), 7.20 (d, J=8.3 Hz, 3H), 6.81 (d, J=8.4 Hz, 2H), 6.10 (s, 1H), 5.59 (s, 2H), 4.26-4.13 (m, 2H), 3.56 (d, J=6.7 Hz, 1H), 3.50 (d, J=9.8 Hz, 5H), 1.90 (d, J=5.4 Hz, 2H). LCMS: MH+ 508 and TR=3.007 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#C/C=C/c1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCc1ccc(F)c(Br)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a solution of (E)-3-(3-bromo-4-fluorophenyl)acrylonitrile (35.0 g, 108 mmol) in ethanol (20 mL) at 0° C. was added sodium tetrahydroborate (16.40 g, 434 mmol). The reaction mixture was allowed to warm to 70° C. and stirred for 4 h. Water was added to quench the reaction, and the organic layer was separated. The water layer was extracted with DCM twice, and the combined organic phase was dried and concentrated. The residue was purified by chromatography to afford the title compound as an oil (20 g, 64.7% yield). LCMS: rt=1.45 min, [M+H+]=228
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20].[C:23](Cl)(=[O:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:23](=[O:25])[CH3:24])[CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20]
Reactant: COC(=O)CCc1ccccc1OCCCCCOC(C)=O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOC(C)=O
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A solution of 4.3 g (13.96 mmol) of 2-[[5-(acetyloxy)pentyl]oxy]benzenepropanoic acid methyl ester and 2.18 g (27.8 mmol) of freshly distilled acetyl chloride in 250 mL of dry dichloromethane was stirred with ice-bath cooling while 7.5 g (56.7 mmol) of anhydrous aluminum chloride was added in one portion. The resulting mixture was stirred at 0°-5° C. for 2 hr before being treated with ice. Work-up with dichloromethane in the usual manner gave an oil which was chromatographed on 100 g of silica gel. Elution with 1:1 hexane-ether afforded 4.22 g (86.4%) of 2-[[5-(acetyloxy)pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester as an almost colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][OH:15].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCC(N)CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCC(CO)Nc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-aminobutan-1-ol according to general procedure 1 providing the amino compound (70 mg, 18%) as yellow solid: Rf=0.53 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J=9.5 Hz, 1H), 7.48 (s, 1H), 6.45 (d, J=9.5 Hz, 1H), 4.51 (d, J=6.3 Hz, 1H), 3.97-3.90 (m, 2H), 3.75-3.72 (m, 1H), 2.65 (br, 1H), 1.76-1.64 (m, 2H), 1.04 (t, 3H); ES-MS: (M+H)=285, 287 m/z.