Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]([C:14]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:15]=1[Cl:21])[OH:13].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+].[F-].[K+].O.O.O.[S-2].[Na+].[Na+]>[Cu].O.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]([C:14]1[CH:19]=[C:18]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:17]=[CH:16][C:15]=1[Cl:21])[OH:13]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(C(=O)O)cc(C)c1C(O)c1cc(I)ccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)O)cc(C)c1C(O)c1cc(-n2ccnc2)ccc1Cl
Reaction time: 30 h

Procedure:
To a suspension of 21 g of α-(2,6-dimethyl-4-carboxyphenyl)-2-chloro-5-iodobenzenemethanol, 5.1 g of imidazole, 13.8 g of potassium carbonate and 120 ml of dimethylformamide are added 0.4 g of potassium fluoride and 0.4 g of copper powder, and the mixture is stirred at 135°-140° C. for 30 hours. After cooling, to the reaction mixture is added 240 ml of water and 0.45 g of sodium sulfide trihydrate. The whole mixture is stirred for 30 minutes. The precipitated copper sulfide is filtered with sellaite under reduced pressure and the filtrate is adjusted to pH 4 with concentrated hydrochloric acid under heating and stirring. The precipitated crystals are collected by filtration, washed with water and then dried. Recrystallization from dimethylformamide gives α-(2,6-dimethyl-4-carboxyphenyl)-2-chloro-5-(1-imidazolyl)benzenemethanol, melting at 318°-320° C. with decomposition, as white crystals in high yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)=[N:12][N:11]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)=[N:12][N:11]=1
Reactant: COc1ccc(-c2nnc(C34CCC(CCCC(C)=O)(CC3)CC4)o2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2nnc(C34CCC(CCCC(C)O)(CC3)CC4)o2)c(Cl)c1
Temperature: 25 °C

Procedure:
5-{4-[5-(2-Chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one (5-H) (0.150 g, 0.373 mmol) was stirred in methanol (5 mL) at 0° C. Sodium borohydride (0.0169 g, 0.448 mmol) was added. The reaction was allowed to stir to room temperature. The mixture was then layered with ethyl acetate (20 mL) and water (20 mL). The ethyl acetate layer was extracted and dried (MgSO4). Solvent was removed in vacuo to afford 5-{4-[5-(2-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol (5-I).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19](C2C3C(=CC=CC=3)N=CC=2)[CH3:20])=[CH:5][CH:4]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2C(N)C)[CH:34]=[CH:33][CH:32]=1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[N:31]=[CH:32][CH:33]=[CH:34]3)[CH3:20])=[CH:5][CH:4]=1
Reactant: CC(N)c1cccc2cccnc12
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(-c2cc(CNC(C)c3cccc4cccnc34)ccc2OC)cc1
Yield: 72 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from 1-quinolin-8-yl-ethylamine (510 mg, 3.0 mmol), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 72% yield (287 mg, 0.72 mmol).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH2:14]([NH2:16])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([NH:16][C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10])[CH3:15]
Reactant: CCN
Reactant: CCOC(=O)c1sc(C)nc1C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNC(=O)c1sc(C)nc1C
Temperature: 140 °C
Reaction time: 25 h
Yield: 50.3 %

Procedure:
3.0 g of ethyl 2,4-dimethylthiazole-5-carboxylate, 7.0 g of ethylamine hydrochloride, 6.0 g of triethylamine, and 100 mL of ethanol were added into a 250 mL of high-pressure reactor. And the reaction mixture was heated to 120-160° C. and stirred for 20 to 30 hours, and then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.5 g N-ethyl-2,4-dimethylthiazole-5-carboxamide which was used in the next step directly without purification.
Reaction SMILES: C(O)(=O)C.O=[CH:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[NH2:17][C@:18]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:19]1[C@@H:20]1[C@@:33]([CH3:36])([CH2:34][CH2:35]2)[C@@:32]2([CH3:37])[C@@H:23]([C@:24]3([CH3:50])[C@@H:29]([CH2:30][CH2:31]2)[C:28]([CH3:39])([CH3:38])[C:27]([C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:26][CH2:25]3)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO.O1CCOCC1>[C:12]([O:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][NH:17][C@:18]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:19]1[C@@H:20]1[C@@:33]([CH3:36])([CH2:34][CH2:35]2)[C@@:32]2([CH3:37])[C@@H:23]([C@:24]3([CH3:50])[C@@H:29]([CH2:30][CH2:31]2)[C:28]([CH3:38])([CH3:39])[C:27]([C:40]2[CH:41]=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][CH:49]=2)=[CH:26][CH2:25]3)[CH2:22][CH2:21]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(NCCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Acetic acid (0.013 mL, 0.221 mmol) and tert-butyl 3-oxopropylcarbamate (38.2 mg, 0.221 mmol) were added to a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.074 mmol) in EtOH (1 mL) and dioxane (1.0 mL) and the mixture was stirred for 2 h at rt. Sodium triacetoxyborohydride (78 mg, 0.368 mmol) was added and the reaction mixture was stirred at 20° C. for two hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (3 mL), washed with 0.1N HCl (5 mL) and brine (5 mL) and extracted with DCM (3×5 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as pale yellow oil (28 mg, 54%). LCMS: m/e 701.51 (M+H)+, 4.0 min (method 10).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
6-Amino-9-benzyl-2-(2-ethoxyethoxy)purine (300 mg, 0.96 mmol) and bromine (2.0 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (256 mg, yield 68%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C@@H:5]([NH:8][C:9]([C:11]1[S:12][C:13]([C:18](=[O:28])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[CH:14][C:15]=1[C:16]#[N:17])=[O:10])[CH2:6][NH2:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:71]1[CH:75]=[CH:74][CH:73]=[C:72]1[C:76](O)=[O:77]>CN(C=O)C.CCOC(C)=O>[CH3:2][O:3][C:4](=[O:29])[C@@H:5]([NH:8][C:9]([C:11]1[S:12][C:13]([C:18](=[O:28])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[CH:14][C:15]=1[C:16]#[N:17])=[O:10])[CH2:6][NH:7][C:76]([C:72]1[S:71][CH:75]=[CH:74][CH:73]=1)=[O:77]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
To a solution of (S)-3-Amino-2-{[3-cyano-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester hydrochloride (0.066 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.03 mL, 0.20 mmol), HBTU (0.030 g, 0.079 mmol), HOBt (0.011 g, 0.079 mmol), and 2-Thiophenecarboxylic acid (0.009 g, 0.069 mmol). The mixture was stirred at room temperature 1.5 h, treated with EtOAc (20 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (30-60% EtOAc in hexane) to give 0.0162 g (16%) colorless oil. MS m/e 512.9 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[O:27])[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([CH:25]([OH:27])[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]ethanone (Example 454, 100 mg, 0.200 mmol) in THF (0.50 mL) was added borane-THF complex (0.700 mL of 1M solution). After stirring at rt for 2 h, the reaction mixture was cooled to 0° C. and was quenched with 3N HCl, and the stirring continued at rt for 1 h. The product was extracted into EtOAc, and the combined extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 column chromatography, eluting with mixtures of EtOAc in hexane, to provide title compound as a racemic mixture. LC/MS: m/e 506.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.59 (1H, d, J=1.9 Hz), 7.56 (1H, d, J=7.3 Hz), 7.35 (1H, dd, J=8.4, 2.0 Hz), 7.12 (21-1, d, J=8.4 Hz), 7.05 (1H, d, J=7.5 Hz), 6.96 (2H, d, J=8.5 Hz), 6.85 (1H, s), 6.74 (1H, d, J=8.3 Hz), 4.95 (1H, q, J=6.4 Hz), 4.80 (1H, br s), 1.57 (3H, d, J=6.7 Hz), 1.26 (9H, s). The racemic mixture was separated into its enantiomers eluting on a Chiracel AD-H column (isocratic 15% EtOH in hexanes, 8 mL/min, 254 nM) with retention time of 22 min and 33 min, respectively. Faster enantiomer E1: LC/MS: m/e 506.0 (M+H)+. Slower enantiomer E2: LC/MS: m/e 506.0 (M+H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:28][NH2:29].C(O)C>>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=4)=[N:29][NH:28][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(C)c1)OCO2
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-methyl-4-nitrobenzoyl)phenylacetate (1.4 g, 3.9 mmol) and hydrazine hydrate (1.0 mL, 18 mmol) in ethanol (25 mL) as a yellow solid (0.65 g, 1.9 mmol, 49%), mp: 275°-277° C. 1H NMR (CDCl3) 8.65 (s, 1H), 8.02 (d, J=8.5, 1H), 7.62 (s, 1H), 7.56 (d, J=8.5, 1H), 6.85 (s, 1H), 6.56 (s, 1H), 6.06 (s, 2H), 3.48 (s, 2H), 2.64 (s, 3H). Anal. Calcd. for C17H13N3O5 : C, 60.18; H, 3.86; N, 12.38. Found: C, 60.22; H, 3.83; N, 12.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:20])[NH2:19].[Cl:21][CH2:22][C:23]([CH2:25]Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]1[S:20][CH:25]=[C:23]([CH2:22][Cl:21])[N:19]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Solvent: Cc1ccccc1
Product: ClCc1csc(-c2cn(CC3CCCCC3)c3c(Cl)cccc23)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid amide (1.74 g, 6.0 mmol), Lawesson's reagent (4.85 g, 12.0 mmol), toluene (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with 20-50% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carbothioic acid amide (1.38 g, 4.50 mmol). A mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carbothioic acid amide (921 mg, 3.00 mmol), 1,3-dichloroacetone (571 mg, 4.50 mmol) in toluene (30 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo, and the obtained crystals were washed with 10% dichloromethane (v/v) in n-heptane to give 7-chloro-3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-1H-indole (587 mg, 1.55 mmol).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[OH:27].[Br:35][CH2:36][C:37](Br)=[O:38]>C(Cl)Cl>[Br:35][CH2:36][C:37]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[OH:27])=[O:38]
Reactant: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 10% (250 ml) was added to a mixture of intermediate (9) (0.072 mol) in DCM (250 ml). Then bromo-acetyl bromide (0.072 mol) was added dropwise at room temperature. The mixture was stirred at room temperature overnight. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of 2-bromo-N-[4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2-[(3-chlorophenyl)hydroxymethyl]phenyl]-acetamide (intermediate 10).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:32]=[C:33]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[NH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:33]2[NH:34][CH:35]=[C:31]([C:15]3[C:6]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[N:32]=2)[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1c2ccc(-c3c[nH]c(C4CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.080 g, 0.20 mmol), tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (0.200 g, 0.61 mmol), sodium carbonate (0.45 g, 0.42 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.010 g, 0.01 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, filtered through a short pad of Celite, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:1, ethyl acetate/petroleum ether) to afford (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-imidazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.050 g, 48%) as a light yellow solid. MS (ESI, pos. ion) m/z 525 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([O-:11])=[O:10].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)[O-])c(Cl)cc2F)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Temperature: 0 °C

Procedure:
First, 0.4 g of methyl. [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate was dissolved in 4 ml of 1,4-dioxane, to which a mixed solution of 1 ml of concentrated hydrochloric acid and 1 ml of water was added under stirring, and the mixture was heated and stirred under reflux for 12 hours. The reaction mixture was then left for cooling, into which ice water was poured, and after addition of ethyl acetate and saturated aqueous sodium chloride solution, the mixture was subjected to phase separation. To the organic layer was added aqueous sodium hydrogencarbonate solution, and the mixture was subjected to phase separation. To the aqueous layer was added aqueous hydrochloric acid solution for acidification, to which ethyl acetate was added, and the mixture was subjected to phase separation. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated to give 0.252 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:7][CH:6]=1)(=O)C.CC1(C)C2CC1CCC2NS(C1C=CC(C#CCCO)=CC=1)(=O)=O>>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][CH2:11][C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)[O:14][C:15]=2[CH:21]=1
Reactant: COc1ccc2cc(C#Cc3ccc(OC(C)=O)cc3)oc2c1
Agent: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Product: COc1ccc2c(c1)OC(CCc1ccc(O)cc1)C2
Yield: 96 %

Procedure:
When the product of Step A was substituted for N-(6,6-dimethyl bicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzenesulphonamide in Example 18, Step C, the similar process (higher pressure of H2) afforded the title compound in 96% yield, as creamy paste. 1H-NMR (CDCl3) 7.25-7.19 (m, 2H); 7.02-6.97 (m, 3H); 6.38-6.35 (m, 2H); 4.81-4.72 (m, 1H); 3.75 (s, 3H); 3.24-3.16 (m, 1H); 2.83-2.73 (m, 3H); 2.27 (s, 3H); 2.13-2.07 (m, 1H); 2.06-1.92 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:33]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1ccccc1)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCNc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-phenylamino-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][O:24][C:25](=[O:58])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH:33]([C:51]2[CH:56]=[CH:55][C:54](Br)=[CH:53][CH:52]=2)[CH2:34][O:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:29][CH2:28]1.[CH3:59][N:60]1C(=O)CCC1>CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[Zn+2]>[CH3:23][O:24][C:25](=[O:58])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH:33]([C:51]2[CH:56]=[CH:55][C:54]([C:59]#[N:60])=[CH:53][CH:52]=2)[CH2:34][O:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:29][CH2:28]1
Reactant: CN1CCCC1=O
Reactant: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C#N)cc2)CC1
Temperature: 50 °C
Yield: 34 %

Procedure:
A round-bottomed flask charged with Pd(OAc)2 (36 mg, 4% moles) and P(o-tol)3 (192 mg, 20% mol) was evacuated and then vented to nitrogen. N-methylpyrrolydone (NMP) (4 ml) was added and the mixture was heated at 50° C. for 30 min. Diethylzinc in hexane (0.29 ml) was added and the mixture was maintained at 50° C. for an additional 30 min. The mixture was cannulated into a flask containing a solution of {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-bromo-phenyl)-ethyl]-piperazin-1-yl}-acetic acid methyl ester (compound 184 prepared at example 1.4.1 above; 2.33 g, 4.0 mmoles) and Zn(CN)2 (0.47 g, 4.0 mmoles) dissolved in NMP (6 ml). The reaction mixture was heated at 60° C. for 3 hours. The eluent was evaporated and the residue was taken up in diethylether. The precipitate was filtered and the organic solution was washed with ammonium hydroxyde, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (eluent: Hex/AcOEt: 75/25 v/v) to give {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-cyano-phenyl)-ethyl]-piperazin-1-yl}-acetic acid methyl ester (compound 317; 0.9 g, 34%).