Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:17][CH:16]=2)[C@H:10]([O:33][CH2:34][C@H:35]2[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][C:44]1[CH:45]=[C:46]([O:54][CH3:55])[C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:43][C:44]2[CH:45]=[C:46]([O:54][CH3:55])[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:53]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:17][CH:16]=2)[C@H:10]([O:33][CH2:34][C@H:35]2[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CCl)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3Cl)cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3Cl)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with the 3-chloromethyl-1-methoxy-naphthalene [example 1) (α)] to yield the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 762.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[O:23][S:28]([CH3:27])(=[O:30])=[O:29])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 0 °C
Reaction time: 20 h
Yield: 93.9 %

Procedure:
A solution of (11β,17β)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one (1.0 g; 2.9 mmole) in dry pyridine (12 ml) was stirred in an ice bath and methanesulfonyl chloride (0.435 ml; 644 mg; 5.6 mmole) was added. The solution was left standing at 0°-5° C. for 20 hours and then poured into ice-cold 20% hydrochloric acid. The mixture was extracted with chloroform, the chloroform solution was washed with water, a dilute sodium bicarbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford a solid (1.20 g). One crystallization from ethyl acetatehexane gave a specimen (1.0 g), melting point 210°-211° C. (dec.), with consistent spectral data.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 65 °C

Procedure:
A mixture of 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide (25 mg, 0.074 mmol), ammonium acetate (57 mg, 0.74 mmol) and sodium cyanoborohydride (9 mg, 0.15 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (20 mg, 80%). LCMS calculated for C17H16ClFNO2 (M−NH2)+: m/z=320.1. found: 320.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1C(=O)c1ccc(F)cc1

Procedure:
Thionyl chloride (1.6 ml) was added to a solution of 2-(4-fluorobenzoyl)benzoic acid (3.6 g) and pyridine (0.03 ml) in benzene (40 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluorobenzoyl) benzoyl chloride (IRνmaxNujol : 1790 cm-1).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH2:21]([NH:27][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCCCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 33.8 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 1.11 g, 4.14 mmol), n-hexylamine (502 mg, 4.96 mmol), Ti(iPrO)4 (2.35 g, 8.27 mmol), TiCl4 (1.0M/DCM, 8.27 ml, 8.27 mmol), and NaBH3CN (520 mg, 8.27 mmol) gives the title compound (495 mg) as a tan solid. Mass spectrum (ion spray): m/z=354 (M+1); (HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.38 (d, 1H), 6.99 (s, 1H), 6.96 (d, 1H), 6.94 (d, 1H), 5.92 (br. s, 2M, 4.24 (t, 1H), 3.01 (m, 1H), 2.83 (m, 1H), 2.73 (t, 2H), 2.45 (m, 1H), 1.88 (m, 1H), 1.53 (m, 3H), 1.32 (m, 5H), 0.89 (t, 3H).
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH3:15])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>C(#N)C>[Cl:37][C:1]1[N:2]=[C:14]([CH3:15])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)NC(C#N)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.25 h

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}acetamide (1.64 g, 7.5 mmol), triphenylphosphine (4.9 g, 18.8 mmol), and carbon tetrachloride (1.8 mL, 18.8 mmol) in acetonitrile (75 mL) was heated at 45° C. for 6 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (80 mL) and 0.5 N NaOH (70 mL) for 15 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-70% EtOAc:hexanes) to give the title compound as a yellow solid, in assumed quantitative yield due to inseparable triphenylphosphine oxide. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.37 (m, 5H), 4.50 (s, 2H), 4.48 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][CH:35]([F:36])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
23 mg (0.91 mmol) 95% Sodium hydride were given to a solution of 200 mg (0.91 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 260 mg (0.91 mmol) 4-chloromethyl-2-[2-(4-difluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. for 12 h. After addition of 20 ml water the resulting precipitate was collected, washed with water (2×10 ml), methanol/water 1:1 (2×10 ml), a small amount of diethyl ether and dried in vacuo at 40° C. to yield 256 mg (60%) of the product as beige powder.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>ClCCl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:26])([F:25])[F:16])=[CH:19][CH:20]=1)(=[O:8])=[O:9]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of trifluoromethanesulphonic anhydride (1.0 g) in dichloromethane (2 ml) was added dropwise to a solution of 4-(trifluoromethyl)phenol (0.5 g) in dichloromethane (10 ml) and pyridine (0.5 ml) at 0° under nitrogen. The resulting suspension was stirred for 1 h at room temperature, diluted with dichloromethane (20 ml) and washed with aqueous sodium carbonate (2N; 20 ml). The dried organic phase was evaporated and the residue was purified by FCC eluting with ether to give the title compound as a colourless oil (710 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]=[CH:10][N:11](C)C)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.N[OH:16]>CO>[Br:1][C:2]1[C:3]([NH:9][CH:10]=[N:11][OH:16])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN(C)C=Nc1nc(Br)cnc1Br
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=CNc1nc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N′-(3,6-dibromo-pyrazin-2-yl)-N,N-dimethylformamidine (18.6 g, 60.80 mmol) in methanol (200 mL) is added hydroxylamine hydrochloride (5.91 g, 85.12 mmol) in one portion. The reaction is stirred at room temperature for 16 hours. The solvent is evaporated and the solid residue is treated with cold (ice cooling) water and collected by filtration. The precipitate is washed twice with water and petroleum ether and dried in vacuo yielding the title compound. 1H -NMR (400 MHz, d6-DMSO) δ(ppm) 7.82 (br s, 1H), 8.21 (s, 1H), 8.34 (m, 1H), 11.17 (br s, 1H). LCMS: Rt 3.17 min (98.7%), m/z (APCI) 295 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][C:39]#[N:40].[F-].[Cs+]>CS(C)=O.O>[C:37]([CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=3[F:33])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1)#[N:36]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: N#CCCN
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NCCC#N)n2)s1
Yield: 13.2 %

Procedure:
A 5 mL microwave tube was charged with N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and 3-aminopropionitrile (163 mg, 2.319 mmol) and CsF (70.5 mg, 0.464 mmol) in dimethyl sulfoxide (3.00 mL) to give a yellow solution at rt under nitrogen. The sealed reaction mixture was microwaved at 90° C. for 30 min. For second time, the sealed reaction mixture was microwaved at 100° C. for 1 h. The reaction was diluted with water and a white solid formed. The reaction was filtered and washed with water. The crude product was chromatographed on silica gel column and eluted with CH2Cl2 with chloroform/methanol/ammonium hydroxide (90:9:1) (5% to 100%) and collected fractions. Water and DCM were added to solid and take to a pH=6 and extracted with DCM (3×). The CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated to obtain N-{3-[5-{2-[(2-cyanoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (35 mg, 12%). MS (ESI): 573 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([Cl:18])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1c[nH]c2ncnc(Cl)c12

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) in CH2Cl2 (6 mL) was added NCS (134 mg, 1.0 mmol). The reaction mixture was refluxed for 18 hours, filtered, and concentrated under vacuum to give the title compound, which was carried on crude. MS (ES+) [M+H]+=189.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1Br)CCNC(=O)C2
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1Br)CCN(CCCCl)C(=O)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 55% sodium hydride dispersion (0.24 g, 5.5 mmol) in oil is added to 7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.35 g, 5 mmol) in dimethylsulfoxide (15 ml) and the mixture is stirred for half an hour at ambient temperature and for 10 minutes at 35°-40° C. The solution is added dropwise, with stirring, to 1-bromo-3-chloro-propane (0.79 g, 5.5 mmol) in dimethylsulfoxide (5 ml). Then the mixture is stirred for 2 hours at ambient temperature, poured into ice water and extracted (4 times) with methylene chloride. The methylene chloride extracts are washed several times with water, dried and evaporated in vacuo. The residue is purified over a silica gel column with ethyl acetate as eluant.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([OH:19])[CH:16]=[C:17]([OH:18])[C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=O)[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:23][N:22]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([OH:19])[CH:16]=[C:17]([OH:18])[C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1c(O)cc(O)cc1S2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc2c(c1)CCc1c(O)cc(O)cc1S2
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
In ethanol, 180 mg of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol (63) was dissolved, and an aqueous solution of 49 mg of hydroxylamine hydrochloride and 100 mg of sodium acetate dissolved in 1 mL of water was added thereto. The mixed solution was stirred at 120° C. for 3 hours, concentrated under reduced pressure and then, extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and then, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1). Upon recrystallization from chloroform-hexane, 120 mg of skin-colored amorphous title compound was obtained (yield 63%). Melting Point: 215.4 to 217.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21](OC)=[O:22])[CH:8]=2)[O:3]1.[CH3:26][NH:27][CH3:28]>>[CH3:1][C:2]1([CH3:25])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([N:27]([CH3:28])[CH3:26])=[O:22])[CH:8]=2)[O:3]1
Reactant: COC(=O)c1ccc2c(c1)C(OC1=CC(=O)CC1)C(C)(O)C(C)(C)O2
Reactant: CNC
Product: CN(C)C(=O)c1ccc2c(c1)C(OC1=CC(=O)CC1)C(C)(O)C(C)(C)O2

Procedure:
A solution of 3.46 g of 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-methoxycarbonyl-3-chromanol in 100 ml of 33% ethanolic dimethylamine solution is heated to 100° in an autoclave for 10 days. The mixture is cooled, worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-dimethylaminocarbonyl-3-chromanol.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH3:30])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:29][CH3:30])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC[C@H](NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CC[C@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl {(3S)-1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]pyrrolidin-3-yl}carbamate (the product from step ii), 0.75 g) in DCM (10 ml) was added TFA slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield: 70 mg
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[NH:8][C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2].[CH3:22][C:23](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:22]([N:8]1[C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4][CH:3]([CH2:1][CH3:2])[C:9]1=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:23]
Reactant: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC1Oc2cccc3nc4c(c(c23)N(CC)C1=O)CCCC4
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of 3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.98 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (2.26 g). The mixture was stirred for 20 mins, bromoethane (5.0 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with sodium bicarbonate solution (250 ml), and extracted twice with ethyl acetate (250 ml). The extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was triturated first with pentane and then diethyl ether to give 4.40 g (80.3%) of 1,3-diethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:11]([NH:17]C1C=CC=CC=1)[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1>>[CH2:9]1[O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:17][CH2:11][C:12]3[O:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][C:4]=2[O:10]1
Reactant: c1ccc(NCc2ccco2)cc1
Reactant: Brc1ccc2c(c1)OCO2
Product: c1coc(CNc2ccc3c(c2)OCO3)c1
Yield: 86.1 %

Procedure:
Using the general procedure, 4-bromo-1,2-(methylenedioxy)benzene (120 μL, 1.0 mmol) was coupled with furfurylaniline (132 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (8:1) as eluent afforded the desired product as a colorless oil (187 mg, 87% yield). Rf=0.5 (hexane/ethyl acetate=5:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)[CH:5]=[CH:4][C:3]=1[C:13]([F:16])([F:14])[F:15]
Reactant: OCCCNc1ccc(C(F)(F)F)c(Cl)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(Cl)n3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 3-{[6-chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 301) (2.0 g, 7.85 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.87 g, 3.93 mmol) in THF (20 mL) were added triphenylphosphine (1.35 g, 5.11 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.30 g, 5.11 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (1.15 g, 64%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, 1H), 6.94 (d, 1H), 6.77 (d, 1H), 6.61 (dd, 1H), 6.42 (d, 1H), 4.16 (q, 2H), 4.01 (t, 2H), 3.55 (q, 2H), 3.55-3.420 (m, 1H), 2.92-2.68 (m, 3H), 2.42-2.30 (m, 2H), 2.08 (qt, 2H), 1.78-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(I)cc4)cc3c2C1

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 17.9 mg (0.051 mMol) 4-iodobenzoyl chloride, the title compound was recovered as a light beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:27]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Br)c2)CC1
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in methylene chloride (1 mL) was allowed to stand for 5 min. To this mixture was added 2-bromobenzoyl chloride (151 mg, 0.687 mmol). The reaction mixture was mixed for 2 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. The filtrate solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column (Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360). The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 45.6 mg (50%) of the title compound.