Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.O>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH:1][CH:2]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]4)(=[O:36])=[O:37])=[CH:33][CH:34]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Nc3cnnc4cc(Cl)ccc34)cc2)C1
Temperature: 3 °C
Reaction time: 0.75 h

Procedure:
3-Amino-1-ethylpiperidine (0.4 ml) in chloroform (15 ml) was treated with anhydrous sodium carbonate (2.94 g) in water (15 ml) and cooled to 3° C. The mixture was vigorously stirred and treated with 4-(7-chloro-4-cinnolinylamino)benzenesulphonylchloride hydrochloride (1.0 g). The dark orange mixture was stirred at 3° C. for 15 minutes, then at room temperature for 45 minutes. During this period the colour lightened considerably. The chloroform layer was separated and dried over magnesium sulphate. The residue on evaporation solidified when triturated with methanol, to give the title compound (0.5 g), m.p. 213°-15° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[I:19])=[CH:5][CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[C:10]([I:19])[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCc1ccc(-c2c(I)oc3nc[nH]c(=O)c23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ccc(-c2c(I)oc3ncnc(Cl)c23)cc1

Procedure:
Stir a suspension of 1.4 g (85% purity, 3.3 mmol) of 5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidin-4(3H)-one in 20 ml (32.9 g, 214.6 mmol) of phosphoryl chloride under reflux for one hour. After concentrating under reduced pressure, add ice-cold water and dichloromethane to the residue. Dry the organic phase over sodium sulphate and filter. Concentrate the filtrate under reduced pressure and dry. 1.0 g (70% purity, 57% of theory) of the target compound is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52](Cl)=[O:53])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)=[O:53])(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(OCc1ccccc1C(=O)Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3COC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chlorocarbonyl-benzyl benzoate there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-benzoyloxymethyl-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 716 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[I:26]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][I:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCI)ccc1Cl
Yield: 88.4 %

Procedure:
2-Chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.1 3,7]dec-1-ylmethyl)-benzamide (5.9 g, Example 6d), iodine (6.2 g, 24.4 mmol), triphenylphosphine (6.4 g, 24.4 mmol) and imidazole (1.66 g, 24.4 mmol) were stirred in dichloromethane (100 ml) at room temperature for 1 h. The reaction was quenched with sat. aq. Na2S2O3 and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography on silica (eluting with EtOAc: isohexane/1:3) to afford the subtitled compound as a pale yellow solid (6.8 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=2[C:14]1=[O:23]>[Pt].C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[CH:16]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:15]2[C:14]1=[O:23]
Reactant: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Agent: [Pt]
Solvent: ClCCl
Product: CC(C)Oc1cc(N2C(=O)C3CCCCC3C2=O)c(F)cc1Cl
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A pressure bottle was charged with 1.01 g (0.003 mol) of N-(2 fluoro- 4-chloro-5-isopropoxyphenyl) -3,4,5,6-tetrahydrophthalimide (see U.S. Pat. No. 4,431,822 for the preparation of this compound), 0.10 g of 5% Pt/C, and 60 ml of methylene chloride, placed on a Paar apparatus, and hydrogenated at 40 psi for 3 hours. Thin layer chromatography showed that the hydrogenation of the double bond was complete. The reaction mixture was filtered through Celite, and solvent removed from the filtrate to give 1.0 g (100% yield) of N-(2-fluoro-4 chloro-5-isopropoxyphenyl)hexahydrophthalimide as a white solid.
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[N:24][C:25]([NH:29][CH2:30][C@@H:31]3[C@H:36]([CH3:37])[CH2:35][CH2:34][CH2:33][N:32]3[C:38]([C:40]3[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=3[N:47]3[N:51]=[CH:50][CH:49]=[N:48]3)=[O:39])=[N:26]2)=[CH:21][CH:20]=1.CB1OB(C)OB(C)O1>>[CH3:37][C@@H:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:38]([C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=2[N:47]2[N:48]=[CH:49][CH:50]=[N:51]2)=[O:39])[C@@H:31]1[CH2:30][NH:29][C:25]1[N:24]=[CH:23][C:22]2[C:27](=[CH:28][C:19]([CH3:1])=[CH:20][CH:21]=2)[N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccc(Br)cc3n2)c1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: CB1OB(C)OB(C)O1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccc(C)cc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using ((2S,3R)-2-(((7-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>C(N(CC)CC)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.[Cu]I>[CH3:24][C:25]([OH:29])([C:27]#[C:28][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1)[CH3:26]
Reactant: C#CC(C)(C)O
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
{4-[5-Bromothiophen-2-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, described in Example 5, (300 mg, 0.76 mmol), PdCl2(PPh3)2 (18 mg, 0.025 mmol), 2-methyl-but-3-yn-2-ol (0.3 ml, 2.53 mmol) and CuI (15 mg) were dissolved in triethylamine (25 ml) and refluxed for 1 hour. The reaction mixture was evaporated, taken up in water and extracted 3 times with TBME. The combined organic phases were dried over sodium sulfate, filtered, and purified via chromatography on silicagel (DCM/MeOH/ammonia:95/5/1 to 90/10/1) to give the title compound as white solid, which was crystallized as HCl-salt from EtOH/HCl. Yield: 150 mg (32%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of ethyl 4-fluoro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (147 mg, 0.48 mmol) in tetrahydrofuran (2.5 mL) was added a solution of lithium hydroxide (20 mg, 0.83 mmol) in water (2.5 mL). After stirring for one hour, the reaction mixture was acidified to pH=2 with 1M HCl, and extracted three times with dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate and rotoevaporated to obtain the title compound (130 mg, 0.47 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[C:12](Cl)([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>C(Cl)Cl>[C:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[C:2]([OH:11])[CH:3]=[CH:4]2)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Cl
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A 2L round bottomed flask was charged with freshly fused zinc chloride (45.0 g), β-naphthol (150.0 g; 1.04 mol) and hexanes (450 ml). The mixture was stirred vigorously while adding t-butyl chloride (150.0 g; 1.62 mol) dropwise over 30 min. When the reaction mixture was gradually heated to reflux, a solution was not obtained. The reaction mixture was cooled to room temperature and 100 ml of CH2Cl2 was added. The reaction mixture was refluxed overnight, cooled and concentrated under vacuum to afford a white solid. The solid was refluxed with 1800 ml of 10% NaOH, filtered, and allowed to cool. The white sodium salt which precipitated was collected by filtration. The solid collected by filtration was stirred with excess 5.0M HC1 and the resulting phenol was collected by filtration and washed with 2 L of water. Recrystallization from heptane afforded 30.67 g of the subtitle compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1>Br>[CH3:25][N:2]([CH3:1])[C:3]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][CH2:5][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:8]1
Reactant: Cc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Agent: Br
Product: Cc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 55 %

Procedure:
(±)-N,N-Dimethyl-N-[4-(3-methyl-1H-indol-2-yl)-1-phenylcyclohex-3-enyl]amine (550 mg, 1.66 mmol) were dissolved in HBr/glacial acetic acid (33% HBr, 20 ml). Sn powder (1 g, 8.5 mmol) was then added to the mixture in portions in the course of 30 min. When the addition had ended, the reaction mixture was stirred for a further 30 min.—For working up, the mixture was concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 2N NaOH (20 ml). The aqueous mixture obtained was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried with Na2SO4 and then concentrated. The residue obtained (530 mg) was recrystallized from methanol (60 ml). N,N-Dimethyl-N-[4-(3-methyl-1H-indol-2-yl)-1-phenylcyclohexyl]amine (less polar isomer) was obtained in this way in a yield of 222 mg (40%, melting point: from 204° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Product: CC(C)CC(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 68) and isovaleryl chloride. m.p.: 183-184° C. (recrystallized from ethyl acetate) 1H-NMR (DMSO-d6) δ: 11.67 (1 H, br s), 10.08 (1 H, br s), 8.69 (1 H, d, J=5.3 Hz), 8.52 (1 H, d, J=9.2 Hz), 8.37 (1 H, d, J=2.1 Hz), 7.57 (1 H, dd, J=2.0, 5.3 Hz), 7.39 (1 H, d, J=2.0 Hz), 7.06 (1 H, dd, J=2.0, 9.6 Hz), 2.46-2.30 (3 H, m), 1.09 (6 H, d, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Mg]Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=[O:12]>C1COCC1>[Cl:1][C:2]1[C:7]([C:11]([OH:12])([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1[Mg]Br
Reactant: CCOC(=O)C(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the Grignard solution prepared above (approximately (2-chloropyridin-3-yl)magnesium bromide (0.564 g, 2.6 mmol) in THF) was added ethyl pyruvate (Sigma Aldrich, 0.289 ml, 2.60 mmol). The resulting mixture was stirred at room temperature for 2 hr. Reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. Material was advanced to the next step. M: 229.9.
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][C:11]1[S:12][C:13]([CH2:16][NH2:17])=[CH:14][N:15]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]4[S:12][C:11]([CH3:10])=[N:15][CH:14]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: Cc1ncc(CN)s1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1ncc(CNC(=O)c2sc(N3CCN(CC4CC4)C3=O)nc2C)s1
Yield: 65 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (2-methylthiazol-5-yl)methanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 65% yield: mp 165-167° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.00 (s, 1H), 6.30-6.27 (m, 1H), 4.60 (d, J=5.4 Hz, 2H), 4.13-4.08 (m, 2H), 3.72-3.66 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.69 (s, 3H), 2.60 (s, 3H), 0.97-0.92 (m, 1H), 0.60-0.53 (m, 2H), 0.27-0.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 166.6, 162.4, 157.6, 155.2, 152.9, 152.0, 117.2, 114.9, 48.6, 42.2, 42.1, 39.9, 19.1, 17.2, 8.9, 3.4; MS (ES+) m/z 392.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC1CCCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCC3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-methylpiperidine (130.86 mg, 1.32 mmol, 3.00 equiv), DIEA (170.28 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:7). This resulted in 60 mg (36%) of methyl 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: O[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:4]1[N:5]([CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH3:3].[CH2:30]([SiH](CC)CC)C.B(F)(F)F.CCOCC>>[CH3:12][O:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:18]=1)[CH2:3][CH3:30]
Reactant: COCCn1cccc1C(C)(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Product: CCC(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)c1cccn1CCOC

Procedure:
The title compound was prepared from N-(4-{1-hydroxy-1-[1-(2-methox-yethyl)-1H-pyrrol-2-yl]-ethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 1) using triethylsilane and boron trifluoride diethyl etherate as described in Example 88 of U.S. application Ser. No. 10/354,922, now U.S. Pat. No. 7,071,358, and provided below as Preparative Example B.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[ClH:20]>O1CCOCC1.CO>[ClH:20].[ClH:20].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.221 g, 0.84 mmol) in dioxane (4 ml) and methanol (1 ml) is added 4M HCl (in dioxane) (0.525 ml, 2.1 mmol) and the reaction mixture is stirred at room temperature overnight. The resulting suspension is filtered and washed with dioxane (3×1 ml) to yield the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:22])([C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([F:13])([F:12])[F:11].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23](=[O:24])[O:22][C:9]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccccc1)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#Cc2ccccc2)(C(F)(F)F)O1
Yield: 40.8 %

Procedure:
A solution of 2-(2-amino-5-chlorophenyl)-4-phenyl-1,1,1-trifluoro-3-butyn-2-ol (2.0 g, 6.1 mmol) and 11.0 g (12.0 mmol) of 1,1'-carbonyldiimidazole in 300 mL of dry THF was stirred under argon at 55° C. for 24 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 200 mL of ether and 400 mL of water. The layers were separated and the aqueous extracted once more with ether. The combined ether extracts were washed with 2×200 mL 10% citric acid and then with brine before drying over MgSO4. Removal of the drying agent and solvent provided 1.5 g (70%) of the crude title compound as an oil. Trituration with ether-hexane afforded 875 mg of (±) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, partial melt at 137°, clear at 147° C. 1H-NMR (CDCl3): δ 6.92 (d, J=8 Hz, 1H), 7.30-7.49 (m, 4H), 7.58-7.65 (m, 3H), 8.99 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[N:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[N:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1nc(C(F)(F)F)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (65 mg), [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol (73 mg) and triphenylphosphine (156 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (140 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from 2-propanol-diisopropyl ether to give the title compound (42 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:9][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2].[Sn].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:9][N:8]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(N)cc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 1-benzyl-4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (15 g, Reference Example 6), tin (25.12 g), hydrochloric acid (230 mL, 3M) and ethanol (230 mL) was heated at reflux temperature for 1 hour. After cooling to room temperature the pH of the mixture was adjusted to 9 by addition of solid sodium carbonate. The mixture was then diluted with water to give a final volume of 1000 mL and then filtered through a pad of celite. The clear filtrate was extracted twice with ethyl acetate (1000 mL). The combined extracts were dried over magnesium sulfate and then evaporated. The crude residue was subjected to chromatography using a Prochrom LC60 column, 40 cm silica bed, 20-45 μm, eluting with a mixture of cyclohexane and ethyl acetate (70:30, v/v) at 100 cm3/minute flow rate. The fractions containing the compound with RF=60/171 (thin layer chromatography plate ref. #05719, Merck KGaA, 64271 Darmstatd, Germany, cyclohexane:ethyl acetate, 70:30, v/v) were pooled and concentrated under reduced pressure (2.7 kPa) to give the title compound (7.22 g) as a yellow oil.