Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:64]1([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([N:67]1[CH2:68][CH2:69][N:64]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:65][CH2:66]1)=[O:6]
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N(CCO)C(=O)c3cc4c(s3)-c3ccccc3OCC4)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a solution of 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid (0.100 g, 0.225 mmol) in 1 mL of THF was added as a whole HATU (0.094 g, 0.248 mmol) and DIEA (0.078 mL, 0.450 mmol). This reaction mixture was allowed to stir at room temperature for 30 minutes. Next, tert-butyl piperazine-1-carboxylate (0.12 g, 0.22 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was taken into a large volume of ethyl acetate, washed with water, then saline and dried (Na2SO4). The organic was then conc. in vacuo to a solid residue and purified by RP-HPLC to give tert-butyl 4-(3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6](N)(=[O:9])C=C.[OH-].[K+].[CH2:13]([CH:19]=[CH:20]C(N)=O)[CH:14]=[CH:15]C(N)=O>O>[CH2:3]=[CH:2][C:1]1[CH:20]=[CH:19][CH:13]=[CH:14][CH:15]=1.[CH:3]1[C:6](=[O:9])[O:5][C:1](=[O:4])[CH:2]=1
Reactant: NC(=O)C=CCC=CC(N)=O
Reactant: C=CC(N)=O
Reactant: C=CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccccc1
Product: O=C1C=CC(=O)O1

Procedure:
20 kg. of acrylic acid and 6 kg. of acrylamide are dissolved in 9.5 kg. of distilled water and the acrylic acid is partially neutralized with 12 kg. of KOH. 0.036 kg. of methylenebisacrylamide as a polyvinyl monomer was added as well as 4 kg. of styrene-maleic anhydride resin (3:1 ratio) to provide an aqueous mixed monomer solution. The mixed monomer solution is mixed with 0.28 kg. of 2,2'-azobisisobutyronitrile, dissolved in 2 kg. of acetone as a polymerization initiator. This mixture at a temperature of 60° C. is transferred on an endless belt (600-700 mm. in width, and 7 m. in length) at a thickness of about 1 cm. The polymerization is initiated promptly on the belt resulting in a solid resin.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH:36][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:18][CH:17]=3)[NH:34][N:35]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COC(=O)c1ccc(N2CCCN(C)CC2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 20421.1 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide was prepared following the procedure as for Example 115, but starting from of methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (0.372 g, 1.5 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.371 g, 1.5 mmol) and 2M trimethylaluminium in toluene (1.875 ml, 3.75 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness and the residual oil crystallised from DCM/diethyl ether to afford the title compound (0. 142 g, 20.42%) as a white solid. 1HNMR (500.13 MHz, DMSOd6+CD3COOD@373K) δ: 2.08-2.15 (2H, m), 2.69 (3H, s), 2.88 (4H, s), 3.11 (2H, t), 3.19-3.24 (2H, m), 3.56 (2H, t), 3.72 (3H, s), 3.74 (2H, t), 6.30 (1H, d), 3.32 (1H,s), 6.49 (2H, s), 6.79 (2H, d), 7.86 (2H, d). MS: m/z 464 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:20].CI.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[N:7]([CH3:28])[C:6]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)n(C)c2c1
Yield: 94.3 %

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-7-(methoxycarbonyl)-2,4-(1H,3H)-quinazolinedione (2.30 g), methyl iodide (2.13 g) and potassium carbonate (2.07 g) in acetone (30 ml) was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated, and the residue was washed with water (60 ml) and methyl t-butyl ether (20 ml) and dried to give the objective compound (2.25 g) as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:40])[CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:30][CH:29]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)CC(=O)c1ccc(CBr)cc1
Product: CC(C)(C)CC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Product: Cl

Procedure:
Use a method similar to the Example 428 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with 1-(4-bromomethylphenyl)-3,3-dimethylbutan-1-one. Use a method similar to the General Procedure 1-4, basic workup, and a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 402 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[C:4]([NH2:16])[N:3]=1.C1(C)C=C(C)C=C(C)C=1S([NH:28]O)(=O)=O.[Br:31][C:32]1[O:36][C:35]([CH:37]=O)=[CH:34][CH:33]=1>>[NH2:16][C:4]1[N:3]2[N:28]=[C:37]([C:35]3[O:36][C:32]([Br:31])=[CH:33][CH:34]=3)[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: Nc1cc(C(=O)c2ccccc2)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Product: Nc1cc(C(=O)c2ccccc2)cc2nc(-c3ccc(Br)o3)nn12

Procedure:
The title compound, MS m/e (%): 383 (M+H+, 100), was prepared in accordance with the general method of example 373 from (2,6-diamino-pyridin-4-yl)-phenyl-methanone, o-mesitylene-sulfonylhydroxylamine, and 5-bromo-2-furaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][CH2:8]2)[NH:3]1.C(OC(N1CCCCC1=O)=O)C1C=CC=CC=1.[H][H].N1CC(=O)NC1=O>C(O)C.[Pd].C(O)(=O)C>[NH:3]1[C:4]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5](=[O:7])[NH:6][C:2]1=[O:1]
Reactant: O=C1NC(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)N1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1CCCCN1C(=O)OCc1ccccc1
Agent: O=C1CNC(=O)N1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1NC(=O)C2(CCNCC2)N1
Temperature: 60 °C

Procedure:
To a solution of 14.6 g (48.1 mmol) benzyl 2,4-dioxo-1,3,8-triaza-spiro[4.5]decan-8-carboxylate (prepared from N-(benzyloxycarbonyl)piperidone by the method from J. Med. Chem. 1995, a, 3772) in 250 ml dry ethanol were added 500 mg 10% Pd/C, and the mixture was filled into an autoclave. After stirring at 60° C. and 10 atm of hydrogen for 3 h no starting hydantoin could be detected by TLC. A precipitate had been formed which was redissolved by addition of 100 ml acetic acid. The catalyst was removed by filtration and the solution was concentrated in vacuo. Aqueous sodium bicarbonate solution was added until the mixture became a clear solution, and the title compound precipitated in two crops upon concentration in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27](OC)[CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]4[N:13]([CH3:12])[C:8](=[O:10])[C:7]5[CH:6]=[N:5][CH:4]=[C:3]([CH3:11])[C:2]=5[N:1]=4)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CN
Reactant: COc1cc(OC2CCN(C3CCC3)CC2)ccc1C=O
Reactant: Cc1cncc(C(=O)O)c1N
Product: Cc1cncc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 4-amino-5-methylnicotinic acid, methylamine and 4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[S:11][C:10]=1[NH2:18].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[Cl:8][C:7]1[C:2]([O:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[C:20]3[NH:18][C:10]2[S:11][C:12]3[C:17]([N:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Nc1nc2cccnc2s1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Clc1cccnc1Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 79 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloropyridine, thiazolo[5,4-b]pyridin-2-yl-amine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [O-]CC.[Na+].ClCCCC(NC1C=C2C(=CC=1)NC=C2CCC[N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([O:36][CH3:37])=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=O.C(Cl)Cl.CO>C(O)C>[CH3:37][O:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)=[N:31][CH:32]=[N:33][CH:34]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NC(=O)CCCCl)cc23)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COc1cncnc1N1CCNCC1
Temperature: 78 °C
Yield: 36.2 %

Procedure:
To a mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (2.3g, 6.3 mmol), and sodium carbonate (0.67 g, 6.3 mmol) in 25 mL of acetone, cooled to 0° C., was added dropwise 4-chlorobutyryl chloride (0.89 g, 6.3 mmol). Additional acetone (10 mL) was added and the suspension was stirred for 19 h at 23° C. The insoluble material was separated by filtration and the acetone was removed in vacuo. The crude material was dissolved in EtOAc, and the solution was washed with water, dried (brine, MgSO4), filtered, and concentrated in vacuo to give crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.98 g, 4.2 mmol, 67%) as a gum. Sodium ethoxide (0.67 mL, 2.1 mmol, 21% in ethanol) was added dropwise to a solution of crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.0 g, 2.1 mmol) in ethanol (5 mL). After the addition, the reaction mixture was heated at 78° C. for 90 min and then cooled to room temperature. The insoluble solid was separated and the filtrate was concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) afforded 1-[3-[5-[2-pyrrolidinone-1-yl]-1-yl]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.33 g, 0.76 mmol, 36%). The free base (0.25 g, 0.58 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.052 g, 0.58 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN, and dried at 70° C. in vacuo overnight to give the title compound (0.17 g, 56%): mp 100°-101° C. Anal. Calcd for C24H30N6O2.1.0 C2H2O4.1.15 H2O: C, 57.26; H, 6.34; N, 15.41. Found: C, 56.90; H, 5.96; N, 15.51.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.CS(Cl)(=O)=O.[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)(=[O:16])[CH:14]=[CH2:15].[OH:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][C:38]2[CH:39]=[C:40]([CH:43]=[CH:44][C:37]=2[O:36][C:31]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13](=[O:16])[CH:6]=[CH2:7])=[CH:35][CH:34]=2)=[O:32])[CH:41]=[O:42])=[O:32])=[CH:34][CH:35]=1)(=[O:16])[CH:14]=[CH2:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2OC(=O)c2ccc(OCCCCCCCCOC(=O)C=C)cc2)cc1
Temperature: -25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
0.6 g of triethylamine and then 0.4 g of methanesulphonyl chloride were added dropwise at -25° C. while stirring to a solution of 1.0 g of 4-(8-acryloyloxyoctyloxy)benzoic acid in 40 ml of tetrahydrofuran. The reaction mixture was stirred at -25° C. for 1 hour, then treated with 0.20 g of 4-hydroxybenzaldehyde and 0.03 g of 4-(dimethylamino)pyridine in 40 ml of tetrahydrofuran, stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of diethyl ether each time. The organic phases were combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from a cyclohexane/ethyl acetate mixture (vol. 8:2) of the fractions which were pure according to thin-layer chromatography gave 0.6 g of 3,4-bis(4-[8-acryloyloxyoctyloxy]phenylcarbonyloxy)benzaldehyd; m.p. (C-I) 56° C.
Reaction SMILES: [CH:1]1([C:4](=[O:29])[C:5](=[CH:25]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:31]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4]2[O:29][N:31]=[CH:25][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(C(F)(F)F)cc1Sc1ccccc1)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (7 g), hydroxylamine hydrochloride (1.24 g) and sodium acetate (1.5 g) in ethanol was stirred at 25° C. for 2 hours. The mixture was then poured into water and extracted with ethyl acetate. The solution was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated and the residue purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and the residue crystallized from cyclohexane to give 3.06 g of 5-cyclopropyl-4-(2-phenylsulphenyl-4-trifluoromethylbenzoyl)isoxazole, m.p. 115° C.
Reaction SMILES: Cl[CH2:2][CH:3]([O:15][CH:16]([CH3:18])[CH3:17])[CH:4](Cl)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[S:19]([O-:22])([O-:21])=[O:20].[Na+:23].[Na+].[S:25](S([O-])=O)([O-:28])(=[O:27])=[O:26].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:2][CH:3]([O:15][CH:16]([CH2:18][S:25]([O-:28])(=[O:27])=[O:26])[CH2:17][S:19]([O-:22])(=[O:21])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:23].[Na+:23]
Reactant: O=S([O-])[O-]
Reactant: CCCCCCCCCC(Cl)C(CCl)OC(C)C
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCC(C)OC(CS(=O)(=O)[O-])CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
The compounds are made substantially as described in Example 2A above, using appropriate substitutions of starting materials (135.5 g of 1,3-dichloro-2-propan-2-yloxydodecane, 98.66 g of sodium sulfite, 34.18 g of sodium meta-bisulfite, 30.66 g of sodium carbonate, 590 g of water, 200° C., 20 hours). Following reaction, the reaction mixture is cooled to ambient temperature and unloaded to afford 865.3 g of light brown reaction product.
Reaction SMILES: [CH:1]([O:3][C:4](=O)[CH3:5])=[O:2].C([O-])=O.[Na+].[CH2:11](O)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17]CC>O>[CH:1]([O:3][CH2:4]/[CH:5]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:2]
Reactant: CC(=O)OC=O
Reactant: CCCCCC/C=C/CO
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCC/C=C/COC=O
Temperature: 60 °C

Procedure:
Acetyl formate (39.6 g, 0.45 mole) is added dropwise to a cooled mixture of sodium formate (6.8 g, 0.10 mole) and trans-2-nonen-1-ol (47.3 g, 0.33 mole). When the addition is complete, the reaction mixture temperature is maintained at 60°C for 7 hours. The mixture is cooled and diluted with water. The organic layer is separated and washed with 5% sodium bicarbonate, water and then dried over sodium sulfate. Trans-2-nonenyl formate, 419 g is obtained on distillation, b.p. 60°-5°C/50-55 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28](Cl)=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1.[OH-].[NH4+:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([NH2:39])=[O:29])=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinoyl chloride (36 mg, 0.066 mmol) in anhydrous THF (1 mL) at room temperature was added 28% aqueous ammonium hydroxide solution (1 mL). The resulting mixture was stirred at room temperature for 10 min. Analysis by HPLC/MS indicated the starting acid chloride had been consumed and the desired product had formed. The reaction mixture was diluted with water and extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 20 mg (57%) of the title compound as a pale yellow powder. HPLC/MS: retention time=2.75 min, [M+H]+=525.1.
Reaction SMILES: [ClH:1].CO[C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1C=CC(CNCCC2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19]C=2C)=CC=1.[CH3:28]C1NC2C(=CC=CC=2)C=1CC[NH2:33]>C(O)C>[C:20]1([NH:19][NH2:33])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl:1][CH2:7][CH2:6][CH2:5][C:4](=[O:27])[CH3:28]
Reactant: Cl
Reactant: Cc1[nH]c2ccccc2c1CCN
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c(C)[nH]c3ccccc23)cc1
Solvent: CCO
Product: CC(=O)CCCCl
Product: NNc1ccccc1

Procedure:
The third embodiment of the present invention is directed to a method of making a starting material useful in the synthesis of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt. In particular, the third embodiment of the present invention is directed to a method of making 2-methyltryptamine comprising the steps of: (a) providing an admixture of phenylhydrazine and 5-chloro-2-pentanone in ethanol at a first temperature; (b) adding ethanol to the admixture and refluxing the mixture; (c) distilling ethanol; (d) adding water to the residual solution; (e) cooling the residual solution to form 2-methyltryptamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][C:25]=2O)[CH2:22][CH2:21][CH2:20]3)([CH2:15][OH:16])[C:7]1=[O:27])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:15][O:16][C:25]3[CH:24]=[C:23]4[C:19](=[CH:18][C:17]2=3)[CH2:20][CH2:21][CH2:22]4)[C:7]1=[O:27])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCC4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
To a solution of ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (4.20 mmol) in anhydrous THF (60.0 mL) was added triphenylphosphine (1.43 g, 5.46 mmol) and diethyl azodicarboxylate (0.95 g, 5.46 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (20.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/4) to give the title compound (0.25 g, 16% in three steps): 1H NMR (300 MHz, CDCl3) δ 7.29 (td, 1H), 7.22-7.17 (m, 1H), 7.07 (t, 1H), 6.81 (s, 1H), 6.78 (d, 1H), 6.65 (s, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.42 (d, 1H), 4.24 (q, 2H), 2.84 (t, 2H), 2.73-2.65 (m, 2H), 2.10-1.95 (m, 2H), 1.29 (t, 3H); MS (ES+) m/z 364 (M+1).