Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(OCCCC)=O)[C:18]1=[O:19])(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:18]1=[O:19])(=[O:10])[CH3:9]
Reactant: CCCCOC(=O)NCCCCCCn1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)c2c1ncn2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCN)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-3-(N-1-butyloxycarbonyl-6-aminohexyl)-7-methylxanthine (1.37 g) in dichloromethane (30 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (20 ml), with water (20 ml), with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine (1.073 g).
Reaction SMILES: C(S[C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1)C1C=CC=CC=1.[ClH:26].ClCl>ClC1C=CC=CC=1>[Cl:26][C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1
Reactant: Cl
Reactant: CN1COCN(Cc2cnc(SCc3ccccc3)s2)C1=N[N+](=O)[O-]
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h

Procedure:
190 g of 3-(2-benzylthio-thiazol-5-yl-methyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine are introduced over a period of 5 minutes, with stirring, into a mixture of 300 g of hydrochloric acid (32%) and 150 g of chlorobenzene. 124 g of chlorine are introduced at 20° C. over a period of 4 hours. After 2 hours, excess chlorine is removed by the introduction of nitrogen, and the phases are then separated. The aqueous phase is adjusted to pH 5 with sodium hydroxide solution (30%) and then filtered, and the filtration residue is washed with water and dried in vacuo at 50° C. The title product is obtained in a purity of 97%.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:33])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@H:35]([CH2:40]O)[C:36]([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C>ClCCl>[CH3:37][C:36]([C@@H:35]1[N:34]2[C:3](=[O:4])[C:5]3[N:6]([CH:7]=[C:8]([C:20]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[O:30])[C:9](=[O:19])[C:10]=3[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:31][C@H:32]2[O:33][CH2:40]1)([CH3:39])[CH3:38]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N21
Yield: 85.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (41 mg, 0.09 mmol) and freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)-3-(1,1-dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40 mg, 85%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (32 mg, 97%) as a tinted white solid. 1H NMR (CDCl3) δ 11.15 (br, 1H), 10.32 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H), 4.58 (m, 2H), 4.36 (m, 2H), 4.21 (m, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 1.02 (s, 9H); ES+MS: 430 (M+1).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:14]1[C:19]2[N:20]=[C:21]3[C:33]4[C:25]([C:26]5[C:31]([N:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:17]=[CH:16][CH:15]=1.[C:34]1([C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:46]2[NH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:34]1([C:47]2[CH:52]=[CH:51][C:50]([N:20]3[C:21]4[C:22](=[CH:23][CH:24]=[C:25]5[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[NH:32][C:33]5=4)[C:18]4[C:19]3=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:49][CH:48]=2)[C:46]2[NH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc2c(c1)N=c1c-2ccc2c1=Nc1ccccc1-2
Reactant: Brc1ccc(-c2cccc3c2[nH]c2ccccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)[nH]c1c(-c3ccc(-n4c5ccccc5c5ccc6c7ccccc7[nH]c6c54)cc3)cccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
In a 100-ml three-necked flask were placed 0.21 g (0.94 mmole) of palladium(II) acetate, 20 ml of xylene, and 0.76 g (3.76 mmoles) of tri-tert-butylphosphine and the mixture was heated at 60° C. with stirring for 30 minutes. The resulting solution was sent into a solution that had been prepared by dissolving 4.61 g (0.0180 mole) of indolo[2,3-a]carbazole, 5.8 g (0.018 mole) of 4-carbazolylbromobenzene, and 7.7 g (0.080 mole) of sodium tert-butoxide in 180 ml of xylene and heated at 60° C. in a stream of nitrogen and the combined solution was heated up to 130° C. and kept at this temperature for 5 hours with stirring. The solution was cooled to room temperature, 200 ml of water was added, and the organic layer was separated and concentrated under reduced pressure to give a crude product. The crude product was purified by crystallization from dichloromethane and ethanol, the solvent was distilled off under reduced pressure, and 4.2 g (0.0084 mole, 47% yield) of 11-(4-carbazolylphenyl)indolo[2,3-a]carbazole was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][O:27][CH3:28])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)(Cl)=O.[CH3:44][O:45][CH2:46][CH2:47][CH2:48][NH2:49]>C1(C)C=CC=CC=1.CC#N>[Cl:1][C:2]1[C:3]([NH:49][CH2:48][CH2:47][CH2:46][O:45][CH3:44])=[N:4][CH:5]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][O:27][CH3:28])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: COCCCN
Reactant: COCc1cc(-c2nc(-c3cnc(O)c(Cl)c3)no2)ccc1-c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COCCCNc1ncc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)cc1Cl
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-5-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-ol (0.702 g; 1.72 mmol) and DIEA (0.24 mL; 1.38 mmol) in toluene (30 mL) was added phosphorus oxychloride (0.192 mL; 2.06 mmol). The reaction mixture was heated at 120° C. for 2 hours. The solvent was removed in vacuo and the residue tritutrated with MeCN to afford a solid. A portion of the solid (0.150 g) combined with 3-methoxypropylamine (0.039 mL; 0.39 mmol) and DIEA (0.104 mL; 0.60 mmol) in MeCN (2 mL). The reaction mixture was heated under reflux for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title compound as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.84 (1 H, d, J=2.0 Hz), 8.40 (1 H, d, J=1.7 Hz), 8.20 (1 H, d, J=2.0 Hz), 8.15 (1 H, dd, J=7.9, 1.9 Hz), 7.36-7.23 (4 H, m), 7.13 (1 H, d, J=7.4 Hz), 6.03 (1 H, t, J=5.2 Hz), 4.22 (2 H, d, J=2.1 Hz), 3.67 (2 H, q, J=6.0 Hz), 3.58 (2 H, t, J=5.67 Hz), 3.40 (3 H, s), 3.32 (3 H, s), 2.08 (3 H, s), 2.01-1.92 (2 H, m). LC/MS: 479 (M+H)+. HPLC (Method E) Rt 5.76 min (Purity: 99.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=C(C#N)[C:11](=[O:14])[NH:12][CH:13]=1.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:19]([C:18]([OH:21])=[O:20])[C:11](=[O:14])[NH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: N#Cc1cc(-c2ccccc2Cl)c[nH]c1=O
Agent: Cl
Product: O=C(O)c1cc(-c2ccccc2Cl)c[nH]c1=O

Procedure:
A mixture of 19.0 g. of 5-(2-chlorophenyl)-1,2-dihydro-2-oxo-3-pyridinecarbonitrile and 1:1 concentrated hydrochloric acid and glacial acetic acid is heated at reflux temperature for 16 hours. A yellow solid is separated which is collected by filtration and is washed with water to give 18.4 g. of the product of the Example as yellow needles, m.p. 299°-303° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]#[N:14])[C:6](=O)[NH:7]2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[C:5]([C:13]#[N:14])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2c(F)cccc2[nH]c1=O
Product: N#Cc1cc2c(F)cccc2nc1Cl

Procedure:
5-Fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (0.80 g, 4.3 mmol) was heated in POCl3 (10 mL) for 3 hrs. The mixture was concentrated and partitioned in ethyl acetate and water. The organic layer was separated, washed with NaHCO3, dried and concentrated. The residue was crystallized from a mixture of hexane and ethyl acetate to give 2-chloro-5-fluoro-quinoline-3-carbonitrile 32-1 as a white solid (0.83 g). 1HNMR (CDCl3), 6, 8.82 (1H, s), 7.83-7.92 (2H, m), 7.33-7.41 (1H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[C:10]1=[O:42].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:34][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC[C@@](N)(CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)C1=O
Yield: 111.7 %

Procedure:
Trifluoroacetic acid (10 mL, 134.63 mmol) was added to a solution of the tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 10) (5.38 g, 10.99 mmol) in DCM (50 mL) at 20° C. and the reaction was stirred until complete. Solid K2CO3 was added to quench the TFA present and the mixture was diluted with water. The phases were separated and the aqueous layer was washed with dichloromethane (×2). The combined organic layers were dried (MgSO4) and the solvent was evaporated to give the (3S)-3-amino-1-methyl-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-2-one (D11) (4.78 g, 12.276 mmol, 111.7% yield) as an amber oil containing some Ph3PO;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:33]([F:36])([F:35])[F:34])=[CH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:37](O)(=[S:39])[CH3:38]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:37](=[S:39])[CH3:38])([C:33]([F:35])([F:34])[F:36])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Reactant: CC(O)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=S)C(CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1)(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material, tert-butyl 5′-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (3.0 g, 6.0 mmoL), was dissolved in dichloromethane (14 mL) and to this solution were added thioacetic acid (2.6 mL, 6.0 eq) and 2 drops of triethylamine and the resulting mixture was stirred at room temperature for 96 h under argon. Solvents were removed under reduced pressure and the crude product was purified via flash silica gel chromatography to yield 1.3 g of tert-butyl 5′-[3-(3,5-dichloro-4-fluorophenyl)-3-thioacetyl-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate. HNMR (400 MHz, CDCl3) δ ppm 8.01 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=5.8 Hz), 5.23 (d, 1H, J=18.5 Hz), 5.17 (s, 2H), 4.35 (d, 2H, J=9.7 Hz), 4.15 (d, 2H, J=9.7 Hz), 3.97 (d, 1H, J=18.5 Hz), 2.33 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.Cl>>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2cccs2)ccc1[N+](=O)[O-]
Agent: Cl
Product: Nc1ccc(Sc2cccs2)cc1N

Procedure:
3.3 G. of 2-amino-1-nitro-4-(thien-2-ylthio)benzene is treated with 16 g. stannous chloride in 16 ml. concentrated hydrochloric acid on the steam bath for 5 minutes. The mixture is cooled, decanted and the gummy residue washed with 16 ml. 6N hydrochloric acid. The residue is dissolved in water, and treated with potassium bicarbonate solution and chloroform. The chloroform is dried and stripped yielding 1,2-diamino-4-(thien-2-ylthio)benzene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[S:5]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:26])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[S:5]1
Reactant: CN1CC(CCCl)Sc2ncccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Sc2ncccc2C1=S

Procedure:
A mixture of 4.3 g (0.017 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]thiazepin-5(4H)-one, 100 ml of toluene and 4.8 g (0.012 mole) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide was refluxed for 3 hr and then extracted twice with dilute sodium hydroxide. The organic layer was concentrated and the residue chromatographed on the high pressure liquid chromatograph using a silica column and 50% ethyl acetate-50% hexane. The yield of title compound was 2 g, m.p. 160°-162° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[CH:11]1[CH2:10][C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:2]([CH3:1])[C:14]=2[CH2:13][CH2:12]1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC2CCc3c(c4ccccc4n3C)C2)cc1
Product: CN(C)C1CCc2c(c3ccccc3n2C)C1

Procedure:
Following the procedure described in Example 18 and using 36.2 g. of 9-methyl-3-tosyloxy-1,2,3,4-tetrahydrocarbazole and 250 ml. of dimetylamine there was otained 9.5 g. of 3-(dimethylamino)-9-methyl-1,2,3,4-tetraydrocarbazole in the form of its hydrochloride salt and which melted at >300°C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[CH2:25][CH2:24]2.[C:31]1([C:37]2[N:38]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[C:39]([Sn](CCCC)(CCCC)CCCC)=[C:40]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[N:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]1([CH:37]2[N:38]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[C:39]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[CH2:25][CH2:24]4)=[C:40]([C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[NH:41]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccncc2)nc(-c2ccccc2)n1COCC[Si](C)(C)C
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCN1C(c2ccc3c(c2)CCC3=O)=C(c2ccncc2)NC1c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Palladium acetate (0.025 g, 0.11 mmol) and triphenylphosphine (0.06 g, 0.22 mmol) were suspended in toluene (1 ml). 5-bromoindanone (240 mg, 1.1 mmol) was then added and the mixture heated to 100° C. for 5 min. The solution was then treated with a solution of the product of Step 3 (0.6 g, 0.94 mmol) in toluene (1 ml) and stirred for 18 hours at 100° C. After cooling the solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with ethyl acetate to afford the title compound (0.25 g, 55%) as a yellow solid; MS(AP+) m/e 482 [M+H]+. Step 5: 5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[C:27]([CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:19])[CH2:35][CH2:36]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.154 g, 0.409 mmol), N,N-dimethylpyridin-4-amine (0.00499 g, 0.0409 mmol), and 4-tert-butylcyclohexanamine (0.0875 ml, 0.490 mmol) in DMF (2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0940 g, 0.490 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 37 mg of the title compound (18% yield).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].Cl>COCCOC>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:24])(=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
To methyl 7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (6.5 g) were added 1,2-dimethoxyethane (130 ml) and 6N hydrochloric acid (65 ml), and the mixture was refluxed at 100° C. for 18 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (5.0 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[OH:8])=[O:6])[CH:2]=[CH2:3].[OH-].[Na+].Cl[C:19](OCC)=[O:20]>O1CCOCC1.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([N:7]2[C:5](=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[C:19](=[O:20])[O:8]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: C=CCNC(=O)N(O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Allyl-3-(4'-chlorophenyl)-3-hydroxyurea (6.0 g.) was dissolved in cooled dioxane (50 ml.) and a solution of sodium hydroxide (1.3 g.) in water (15 ml.) was added thereto. Ethyl chloroformate (3.2 g; 2.9 ml.) was added dropwise at 10°-15° C. with stirring and the stirring continued for about 1/2 hour after the addition was completed. The reaction mixture was poured into cold water (300 ml.), stirred and filtered to separate the precipitate. The precipitate was recrystallized from ethanol and dried in vacuo at room temperature to yield 2-(4'-chlorophenyl)-4-allyl-1,2,4-oxadiazolidine-3,5-dione as white needle-like crystals melting 56°-57° C. and having the following elemental analysis as calculated for C11H9ClN2O3 :
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[NH:19][N:18]=1>>[F:27][C:16]([F:15])([F:26])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N:19]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][C:10]3=[O:14])=[CH:4][CH:3]=2)[N:18]=1
Reactant: O=C1CCCN1Cc1ccc(I)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: O=C1CCCN1Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-[(4-iodophenyl)methyl]-2-pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 19.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CCCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 87.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 122c by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (23.3 g, 37.8 mmol) prepared in Example 142b, triethylsilane (28.3 mL, 177 mmol), trifluoroacetic acid (50 mL) and dichloromethane (500 mL), to yield the title compound (15.4 g, 88%) as a colorless solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH3:35]
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A163) and acetyl chloride the title compound is obtained as colorless solid.