Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[Br:12][Si](C)(C)C>C(Cl)(Cl)Cl>[Br:12][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: OC1CCc2cc(Br)ccc21
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)CCC2Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a nitrogen-purged flask was added 100 mg (0.469 mmol) of 5-bromoindan-1-ol from Step A and 3 mL of anhydrous chloroform, followed by 0.096 mL (0.704 mmol) of bromotrimethylsilane. The reaction mixture was stirred at ambient temperature overnight and concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated to give a brown oil which was used without further purification. Mass spectrum (MS): m/z 195, 197 (M+1-HBr), 116 (M+1-2HBr).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:26]([O:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([O:44][CH3:45])[CH:43]=2)[C:39]#[N:40])=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:41]=[C:42]([O:44][CH3:45])[CH:43]=[C:36]([O:35][C:26]3[C:25]([Cl:24])=[CH:30][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:28][N:27]=3)[CH:37]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: COc1cc(C#N)cc(Oc2ncc(C(F)(F)F)cc2Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(Oc2ncc(C(F)(F)F)cc2Cl)cc(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 3-(3-chloro-5-trifluoromethylpyridine-2-yloxy)-5-methoxybenzonitrile (0.80 g), anhydrous iron (III) chloride (0.80 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [NH2:1][C:2](=[N:37][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:41]([OH:44])(=[O:43])[CH3:42]>[Pd].C(Cl)Cl>[C:17]1([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]([NH:8][C@@H:7]([C:24]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH3:36])=[CH:32][CH:33]=2)=[O:25])[CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:1])[NH2:37])=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:41]([O-:44])(=[O:43])[CH3:42]
Reactant: CCOc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: ClCCl
Product: CC(=O)[O-]
Product: CCOc1ccc(CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 97 %

Procedure:
Prepared analogously to Example 1c) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-N-[(4-ethoxyphenyl)-methyl]-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 97% of theory. Colourless crystals, mp. 97°-100° C. and Rf 0.75. IR (CH2Cl2): 1665 cm-1 (C=O) 1515 cm-1 (amide-II) ESI-MS: (M+H)+ =502
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:8][CH2:7][CH2:6]1)=O.C(O)(=O)C.[CH:13]([NH2:15])=[NH:14]>C(O)CO.O>[CH:5]1([C:3]2[N:14]=[CH:13][NH:15][CH:2]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: N=CN
Reactant: O=C(CBr)C1CCC1
Solvent: OCCO
Solvent: O
Solvent: CC(=O)O
Product: c1nc(C2CCC2)c[nH]1
Temperature: 135 °C
Yield: 18.6 %

Procedure:
A mixture of 2-bromo-1-cyclobutylethanone (27.2 g, 154 mmol) and formamidine acetate (80.0 g, 768 mmol) in ethyleneglycol (150 mL) was heated to 135° C. for 18 h. The mixture was then diluted with H2O and then continuously extracted with Et2O for 18 h. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by distillation in a Kugelrohr oven and flash chromatography (SiO2, DCM to DCM/MeOH 9:1) afforded the title compound (3.5 g). UPLC-MS: MS 123.1 (M+H+); UPLC rt 0.36 min.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@H:11]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:15][NH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 4c (0.12 g, 0.394 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 5 h. The solvent was removed by evaporation. Ether (10 mL) was added to the residue. The crude product was collected by filtration, washed with ether, and dried under vacuum. MS m/z (M+H+) 205.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:10].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C=O.[CH3:19]C(C)=O>C(O)C>[ClH:10].[N:11]1([CH2:19][CH2:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)=O
Reactant: C1CCNCC1
Reactant: CC(=O)c1ccccc1
Agent: C=O
Agent: Cl
Solvent: CCO
Product: O=C(CCN1CCCCC1)c1ccccc1
Yield: 75.4 %

Procedure:
A mixture of 120 g of acetophenone, 133 g of piperidine hydrochloride and 50 g of paraformaldehyde in 120 ml of ethanol was refluxed for 6 hours. The mixture was then allowed to stand for cooling to soldify. The resulting solid was crushed after addition of 400 ml of acetone, and then collected by filtration. The collected solid was washed successively with acetone and hexane and dried to obtain 191.6 g (yield: 75.4%) of the subject compound as a white scaly product.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Na+].Cl>C(#N)C.O>[C:1]([C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(OC)c(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0.80 g portion of methyl 5-cyano-2,4-dimethoxybenzoate was dissolved in 8 ml of acetonitrile and 5 ml of water, and 7 ml of 2N sodium hydroxide aqueous solution was added, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction solution was poured into 2N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give 0.65 g of 5-cyano-2,4-dimethoxybenzoic acid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[C:4]([C:15]([O:17]C)=[O:16])=[CH:3][CH:2]=1.[OH-].[K+]>CO>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[C:4]([C:15]([OH:17])=[O:16])=[CH:3][CH:2]=1.[CH2:5]([O:6][CH2:7][CH3:8])[CH3:4]
Reactant: COC(=O)c1cccc2c1Oc1ccccc1N2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOCC
Product: O=C(O)c1cccc2c1Oc1ccccc1N2

Procedure:
A solution of methyl phenoxazine-4-carboxylate (0.241 g, 1 mmol) in methanol (25 ml) containing potassium hydroxide (0.560 g) was heated at reflux for 1 hour. The solvent was removed in vacuo and 5% hydrochloric acid added to the residue. The product was extracted with ethyl acetate, washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The solid residue was homogeneous by TLC over silica gel (ethyl acetate:hexane 1:3) and was different from the monocarboxylic acid described by Gilman and Moore. After recrystallization from benzene:ethyl ether phenoxazine-4-carboxylic acid, mp 181°-182° C. was obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH2:8][CH:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.Cl.[CH3:15]O>>[CH3:15][O:11][C:10](=[O:12])[CH:9]([NH2:13])[CH2:8][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([OH:7])[CH:4]=1
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)Cc1cccc(O)c1

Procedure:
DL-m-Tyrosine (1 g) was stirred in a 3M solution of HCl in MeOH (10 ml) for 2 h at RT The solvent was removed and HV drying afforded 1.43 g of the desired compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][C:23]=1[F:34])[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[CH:24][C:23]=1[F:34])[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1F
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1F
Temperature: 120 °C
Yield: 18.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (76 mg, 0.348 mmol), N-ethyl-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (100 mg, 0.348 mmol), (cyanomethyl)trimethylphosphonium iodide (127 mg, 0.521 mmol) and N,N-diisopropylethylamine (0.303 ml, 1.738 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 120° C. for 3 h. The reaction mixture became a dark brown suspension. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)-N-ethyl-2-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (28.5 mg, 0.063 mmol, 18.12% yield) as a brownish solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.83-2.02 (m, 3 H) 2.18 (dd, J=6.44, 4.17 Hz, 1 H) 2.44-2.49 (m, 4 H) 2.81-3.01 (m, 4 H) 3.23-3.32 (m, 2 H) 3.34-3.44 (m, 3 H) 3.52-3.64 (m, 1 H) 3.93-4.01 (m, 1 H) 6.91 (td, J=8.21, 2.53 Hz, 1 H) 6.97 (d, J=1.77 Hz, 1 H) 7.00 (dd, J=11.37, 2.53 Hz, 1 H) 7.62 (d, J=1.52 Hz, 1 H) 7.67 (dd, J=8.46, 7.20 Hz, 1 H) 8.86 (t, J=5.43 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:30]=[C:29](C(C)C)[CH:28]=[C:27]([CH:34]([CH3:36])[CH3:35])[C:5]=1[O:6][CH2:7][C:8]([C:10]1[C:11]([CH:24]([CH3:26])[CH3:25])=[C:12]([O:19][S:20](=[O:23])(=[O:22])[NH2:21])[C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1)=[O:9])[CH3:3].C(C1C=C(C(C)C)C=C(C(C)C)C=1O)(C)C.C(C1C=CC=C(C(C)C)C=1O)(C)C>>[CH3:36][CH:34]([C:27]1[CH:28]=[CH:29][CH:30]=[C:4]([CH:2]([CH3:3])[CH3:1])[C:5]=1[O:6][CH2:7][C:8]([C:10]1[C:11]([CH:24]([CH3:25])[CH3:26])=[C:12]([O:19][S:20](=[O:22])(=[O:23])[NH2:21])[C:13]([CH:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=1)=[O:9])[CH3:35]
Reactant: CC(C)c1cc(C(C)C)c(OCC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1
Agent: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Agent: CC(C)c1cccc(C(C)C)c1O
Product: CC(C)c1cccc(C(C)C)c1OCC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 46, except that 2,4,6-triisopropylphenol was replaced with 2,6-diisopropylphenol, mp 108°-110° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:13][N:12]=1)([O:3][CH3:4])=[O:2].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>O1CCCC1>[C:26]([N:13]1[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:15][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])=[N:12]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)n(C(C)=O)n1

Procedure:
A mixture of 30 g 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, 0.30 g sodium hydride and 0.8 g acetyl chloride in 50 ml anhydrous tetrahydrofuran (THF) is stirred and refluxed overnight. The reaction mixture is filtered and the THF is removed from the filtrate to yield 1-acetyl-3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole.
Reaction SMILES: O[CH2:2][N:3]1[C:7](=[O:8])[CH2:6][CH:5]([S:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[C:4]1=[O:25].CS(Cl)(=O)=O.[C:31]([C:35]1[CH:36]=[C:37]([SH:46])[CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])([CH3:34])([CH3:33])[CH3:32].[OH-].[Na+]>C(OC(=O)C)C.CCCCCCC.C(N(CC)CC)C>[C:31]([C:35]1[CH:36]=[C:37]([S:46][CH2:2][N:3]2[C:7](=[O:8])[CH2:6][CH:5]([S:9][C:10]3[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=3)[C:4]2=[O:25])[CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(SC2CC(=O)N(CO)C2=O)cc(C(C)(C)C)c1O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCN2C(=O)CC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)cc(C(C)(C)C)c1O
Yield: 44.2 %

Procedure:
The procedure of Example 3 was repeated using 10.0 grams of N-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenylthio)succinimide, 2.33 ml of methanesulfonylchloride, 5.72 ml of triethylamine, 6.52 grams of 3,5-di-tert-butyl-4-hydroxybenzene thiol and 1.09 grams of sodium hydroxide. Flash column chromatography (SiO2, 5:1 heptane:ethylacetate) afforded 7.09 grams of product as white solid, m.p. 138°-140° C.
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+:16]>CO>[NH2:16][C:6]([C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)=[CH:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)c1cccs1
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C=C(N)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of 17.83 g (0.09679 mol) of methyl 2-(2-thenoyl)acetate in 180 ml of methanol, 36.62 g (0.5807 mol) of ammonium formate was added, and the resulting mixture was heated under reflux for 38 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated off under reduced pressure. To the residue, 100 ml of ethyl acetate and 100 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, washed with 40 ml of water and with 40 ml of a brine successively and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective methyl 3-amino-3-thiophen-2-yl-acrylate (15.80 g, colorless liquid). The yield was 89.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH:17]([CH3:18])[CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:16])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Reactant: CCC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)C2=CC(C)=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (76 mg) in DMF (3 mL) were added 4-sec-butylaniline (0.069 mL), HOBt (67 mg), and EDCI HCl (84 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (10 ml), and the resulting precipitate was collected by filtration. The obtained solid was recrystallized from DMSO-ethanol to give the title compound (114 mg) as pale-yellow crystals.
Reaction SMILES: [Cl:1]C(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[N:8]([CH3:16])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[NH2:20][C@@H:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([O:31][C:32]2[CH:33]=[CH:34][C:35]3[N:36]([C:38]([C@H:41]4[N:45]([CH3:46])[CH2:44][C@@H:43]([N:47]([CH3:49])[CH3:48])[CH2:42]4)=[N:39][N:40]=3)[CH:37]=2)[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.Cl>O1CCOCC1.CC#N>[ClH:1].[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C@@H:41]5[CH2:42][C@H:43]([N:47]([CH3:49])[CH3:48])[CH2:44][N:45]5[CH3:46])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:17])[N:8]([CH3:16])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CN(C)[C@H]1C[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)N(C)C1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1C[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)N(C)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(5-Tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US2004/0192653, which is incorporated herein by reference in its entirety; 242 mg, 0.74 mmol) was treated with a solution of Intermediate 38d (300 mg, 0.74 mmol) in 1,4-dioxane (5 mL) then DIPEA (185 μL, 1.1 mmol) was added. The mixture was stirred at 50° C. overnight. The mixture was evaporated in vacuo and the residue purified by HPLC (Method 6, 20-40% MeCN in H2O, 0.1% HCO2H over 30 min) to give a colourless glass that was dissolved in MeCN and treated with 1N HCl (550 μL, 1 eq.). The volatiles were evaporated to drieness under reduced pressure affording a colourless glass that upon trituration with ether gave a solid. The solid was collected by filtration, washed with ether and dried at 50° C. in vacuo to give the title compound as an off white solid (346 mg, 74%). LCMS (Method 5): Rt 3.01 min, m/z 586.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.81-2.15 (5H, m), 2.16-2.24 (2H, bs), 2.42-2.52 (4H, br s, partially obscured by DMSO), 2.74-2.80 (6H, s), 3.45-3.53 (2H, m), 3.56 (3H, s), 3.97-4.06 (1H, m), 4.79-4.88 (1H, m), 5.54 (1H, t, J 4.3 Hz), 6.00 (1H, s), 7.08 (1H, d, J 8.4 Hz), 7.22-7.27 (1H, m), 7.33-7.39 (4H, m), 7.77 (1H, d, J 9.3 Hz), 8.45 (1H, bs), 8.60 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)#[CH:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:19]=[CH:18]\[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C#Cc1cccnc1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2cccnc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (113 mg, 0.50 mmol; Example 2B) and 3-ethynylpyridine (0.206 g, 2.0 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound as one of two isomers: 1H NMR (300 MHz, methanol-d4) δ ppm 1.62-1.76 (m, 2H), 1.81-1.96 (m, 2H), 2.38 (s, 3H), 2.92-3.08 (m, 3H), 3.09-3.22 (m, 2H), 4.21 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.84-7.03 (m, 3H), 7.14-7.30 (m, 3H), 8.02 (d, J=2 Hz, 1H), 8.26 (dd, J=5, 2 Hz, 1H); MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([CH:14]([F:16])[F:15])[C:5]=1[C:17]([O:19][CH3:20])=[O:18].[OH-:22].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[C:8]([C:9](=[C:4]1[CH:5]([CH3:17])[CH2:6][CH2:14][O:22]1)[C:9]1[C:4]([CH2:3][CH:2]([CH3:21])[CH3:1])=[C:5]([C:17]([O:19][CH3:20])=[O:18])[C:6]([CH:14]([F:16])[F:15])=[N:7][C:8]=1[C:10]([F:12])([F:13])[F:11])#[N:7]
Reactant: COC(=O)c1c(CC(C)C)cc(C(F)(F)F)nc1C(F)F
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCC2C)c1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 5.0 g (14.3 mmol) of 5-(cyanomethyl)-4-(2-methylpropyl-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example d, above, 5.0 g (34.9 mmol) 1-methyl-4-chlorobutyryl chloride, 0.37 g benzyltriethylammonium chloride, and 150 mL dichloromethane was added 82 mL 50% NaOH. The solution was stirred at room temperature for 2 hours. The reaction was then quenched with ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered through silica gel and concentrated to give 5.2 g of crude product. Purification by chromatography using 20% ethyl acetate in hexanes yielded 3.1 g of the desired product as a yellow oil, a 51% yield. nD25 1.4887.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][C:16]([CH3:20])=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:24]1[CH2:25][CH2:26][N:21]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=2)[CH2:22][CH2:23]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)nc1C
Yield: 103.3 %

Procedure:
Using 2-bromo-4-chlorobenzoic acid (1 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (0.87 g) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.85 g) was obtained.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C([O:21]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>C1COCC1>[C:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([OH:21])=[CH:8][CH:9]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Agent: OO
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)Oc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Sec-butyllithium (53.2 mmoles, 41 ml of 1.3M in hexane) was added dropwise at -78° C. to 4-bromo-t-butoxybenzene (53.2 mmoles, 12.2 g) in 200 ml THF, stirred at -78° C. for 1 hour, and added slowly to a solution of triisopropylborate (58.5 mmoles, 11.0 g) in 50 ml THF while maintaining the temperature below -60° C. The mixture was allowed to warm gradually to -20° C. Chilled acetic acid (80 mmoles, 9.6 ml) was added. Hydrogen peroxide (58.5 mmoles, 5.9 ml of 30% diluted with 5 ml water) was added dropwise over 15 minutes while maintaining the temperature below 0° C. After stirring 10 minutes, the solution was washed with ammonium sulfate solution, dried, and concentrated. The residue was triturated with hexane and filtered to yield 4.2 g of 4-t-butoxyphenol. (MS).