Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.I[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.CN1CCOCC1.Cl>O1CCOCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
1.02 g (5 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine, 1.24 g (5 mmol) of 4-iodobenzoic acid, 820 μl (7.5 mmol) of N-methylmorpholine, 360 mg (2.5 mmol) of Cu2O and 15 ml of dioxane were introduced successively into a round-bottomed flask. The entire contents were heated at reflux for 24 hours, the reaction medium poured into 15 ml of 5N hydrochloric acid, the precipitate filtered and the latter washed with water.
Reaction SMILES: N[C:2](N)=[O:3].[C:5]1([CH:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:22]3[C:23]([NH2:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC(Cl)Cl>O>[C:33]1([CH:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]3[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=4[NH:32][C:2]3=[O:3])[CH2:14][CH2:13]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: NC(N)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 190 °C

Procedure:
A mixture of 5.4 parts of urea and 13.7 parts of N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-4-(trifluoromethyl)-1,2-benzenediamine is stirred and heated for 4 hours at 190° C. The reaction mixture is cooled to room temperature and diluted with water. After the addition of trichloromethane, the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one; mp. 152.7° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:21]=[CH:20][C:11]([CH2:12][O:13]C2CCCCO2)=[CH:10][C:9]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([C:8]1[CH:21]=[CH:20][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(COC2CCCCO2)ccc1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(CO)ccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-(4-benzyl-3-methylbenzyloxy)tetrahydropyran (2.9 g, 0.01 mol) was dissolved in methanol (50 ml). To the obtained solution was added 10% hydrochloric acid (10 ml), and the mixture was stirred at room temperature for 1 hour. After distilling methanol, saturated aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. After washing with saturated aqueous sodium hydrogencarbonate solution, water and saturated aqueous sodium chloride solution, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled away to give the title compound (2.2 g, 0.01 mol).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[C@@H:34]([F:39])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:34]([F:39])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=N[C@H]1CC[C@H](N)[C@@H](F)C1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N=[N+]=[N-])C[C@H]1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1S*,2S*,4S*)-4-azido-2-fluorocyclohexanamine hydrochloride (example C23) the title compound is obtained as pale yellow foam.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([NH:25]C1CCCCO1)=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2].Cl.[O:33]1CCOCC1>>[C:1]([NH:4][C@H:5]([C:23]([NH:25][OH:33])=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NC1CCCCO1
Reactant: C1COCCO1
Agent: Cl
Product: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Reaction time: 1 h
Yield: 32 %

Procedure:
The product from Example 9f (1.0 mmol, 450 mg) was dissolved in dioxane (5 mL). Six normal HCl (0.5 mL) was added, and the mixture was stirred one hour. Concentration followed by chromatography afforded the title compound as a glass (120 mg, 32%). MS MH+ calcd. for C17H18N2O6S 378, found 379.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:36]2[C:31]([CH:32]=[N:33][C:34](OS(C(F)(F)F)(=O)=O)=[N:35]2)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:34]3[N:33]=[CH:32][C:31]4=[CH:30][CH:29]=[C:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[O:21][CH3:20])[N:36]4[N:35]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)C4)cc3)nn12

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 3-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) δ 9.4 (s, 1H), 8.9 (s, 1H), 7.8 (d, J=7.5 Hz, 1H), 7.6 (d, J=8.5 Hz, 2H), 7.45 (t, 1H), 7.2 (d, J=8.5 Hz, 1H), 7.1 (m, 3H), 6.9 (dd, J1=J2=4.6 Hz, 2H), 3.8 (s, 3H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 2H), 3.2 (t, 1H), 2.1 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[C:4]([C:15](=[O:18])[CH2:16][CH3:17])=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Product: CCC(=O)c1c(OC)cc(OC)cc1C(=O)O

Procedure:
This compound is synthesized by reacting methyl 3,5-dimethoxybenzoate with propionyl chloride via the Friedel-Crafts reaction, followed by saponification of the ester obtained, according to the method described in 2.1. It is used in crude form in the following reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a mixture of 6-bromo-3-(4-fluorophenyl)-imidazo[1,2-a]pyridine (intermediate E) (100 mg, 344 μmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (119 mg, 412 μl) in 1,2-dimethoxyethane (2 ml), was added 1M Na2CO3 (859 μl, 859 μmol), and the reaction mixture was purged with argon for 10 min in an ultrasonic bath. Afterwards tetrakis(triphenylphosphine)palladium(0) (39.7 mg, 34.4 μmol) was added, and the stirred reaction mixture was heated under reflux conditions for 17 h. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (190 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH, 0-20%) and trituration (diethyl ether) to yield the title compound as an off-white solid (40 mg, 31%), MS (ISP) m/z=373.4 [(M+H)+], mp 172° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)c(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (309 mg, 0.77 mmol) (from example 143, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.203 mL, 0.77 mmol) in water (0.500 mL) was added and the mixture was stirred at −40° C. for 20 min. Hydroxylamine (50% in water, 0.047 mL, 0.77 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (3.98 mL, 23.87 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)-piperidine-1-carboxylate (111 mg, 38.9%) was isolated. MS m/z 371 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](OCC)=[O:13])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 83.1 %

Procedure:
Ethyl 2-chloro-4-(4-fluorophenyl)-3-quinolinecarboxylate (12.91 g) is dissolved in 200 ml of dichloromethane at -78° C. under an atmosphere of nitrogen. A solution of diisobutylaluminum hydride (DIBAL) (97 ml, 2.5 equivalents) in dichloromethane is added dropwise and the reaction stirred for 3.5 hours at -78° C. The reaction is quenched by addition of a saturated solution of sodium sulfate (20 ml) and removing the cooling bath. The gelatinous mass is filtered through Celite, washed with hot ethyl acetate, and the filtrate evaporated to give 9.36 g of 2-chloro-4-(4-fluorophenyl)-3-quinolinemethanol as a white solid; mp 159°-160° C.; 1H NMR (chloroform-d): δ 8.07 (d, 1H), 7.79-7.70 (m, 1H), 7.53-7.22 (m, 6H), 4.67 (d, 2H), 2.24 (t, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][O:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH2:22][F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1cnc(OCF)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(OCF)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(fluoromethoxy)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=446.5 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNCCN2CCOCC2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.12 mL, 0.69 mmol) and 4-(2-aminoethyl)morpholine (0.11 mL, 0.84 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (51 mg, 34% yield).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2Sc2ccccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
20 g (0.1 mol) of phenothiazine followed by 14.3 ml (2 eq.) of acetyl chloride are added to a 500 ml flask containing 200 ml of toluene. The heterogeneous reaction mixture is stirred for 1 hour at 50° C. After concentration to dryness, the precipitate is taken up in a minimum of isopentane and filtered. After drying, 24 g of a beige solid is obtained with a quantitative yield. Melting point: 210-211° C.
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([NH:36][C:37]([NH:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: CC[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccccc4)cc23)CC1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride mono-ethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 1.37 mL (12.6 mMol) phenyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.40 gm (70%) N-phenyl-N′-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea. This material was dissolved in methanol and to it was added an equivalent of methanolic hydrogen chloride. The solution was then concentrated under reduced pressure and the residual oil crystallized from ethanol to give the title compound.
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:13][C:12]([O:16][CH3:17])([O:14][CH3:15])[CH2:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-:21].[K+].[K+].O>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:18]([NH2:19])=[O:21])[CH2:13][C:12]([O:14][CH3:15])([O:16][CH3:17])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC1(OC)CC(C#N)(c2ccc(Br)cc2)C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC1(OC)CC(C(N)=O)(c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 488.5 %

Procedure:
Hydrogen peroxide (2.05 ml, 20.07 mmol) was added over 2 h to a stirred mixture of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile (3.18 g, 10.74 mmol) and Potassium carbonate (0.297 g, 2.15 mmol) in DMSO (11 ml) at 40 degree under a nitrogen atmosphere. After the addition, the reaction mixture was heated to 80 degree for 3 h. The reaction mixture was allowed to cool down to room temperature and water (30 ml) was added. The reaction mixture was extracted with ethyl acetate (3×20 ml). The combined organic phase was washed with water (2×30 ml), brine (30 ml), concentrated to give light yellow oil (3.3 g). 1H NMR (500 MHz, CDCl3) 7.40 (d, 2H), 7.11 (d, 2H), 5.89 (br, 1H), 5.58 (br, 1H), 3.12 (s, 3H), 3.02 (s, 3H), 2.97 (d, 2H), 2.52 (d, 2H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[CH2:6]([OH:9])[CH:7]=[CH2:8]>O>[CH3:1][C:2]([O:9][CH2:6][CH:7]=[CH2:8])([CH2:4][CH3:5])[CH3:3]
Reactant: CC=C(C)C
Reactant: C=CCO
Solvent: O
Product: C=CCOC(C)(C)CC

Procedure:
100 gms 2-methylbut-2-ene, 300 gms allyl alcohol and 10 gms Amberlyst 15 resin were charged to a 1-liter flat-bottomed flask containing a magnetic follower and fitted with a stopper incorporating a gas inlet tube dipping below the surface of the liquid in the flask and with an exit tube leading from the gas space to a Drechsel bottle filled with water. The flask was purged with nitrogen and then placed in a water bath at 30° C. on a magnetic stirrer. The contents of the flask were maintained at this temperature for 16 hours and then filtered. After washing 5 times with deionised water, each time at an approximately 1:1 ratio by volume, in order to remove the bulk of the unreacted allyl alcohol, the resulting organic layer was dried over anhydrous sodium carbonate and the ether was purified by distillation. The yield was 137 gms (74.9% based on the olefin), b.p. 125°-127° C. at 770 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](S(C(F)(F)F)(=O)=O)[C:5]([S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:4][C:3]=1[Cl:22].[CH3:23][S:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])[C:6]([C:28]2[CH:29]=[CH:30][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1cc(Cl)c(Cl)cc1S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1ccc(-c2cc(Cl)c(Cl)cc2S(=O)(=O)C(F)(F)F)cc1
Yield: 67.2 %

Procedure:
Under nitrogen, 5 g (4.3 mmol) of Pd(PPh3)4 was added to a stirred solution of 7.9 g (17.8 mmol) of 1,2-dichloro-4,5-bis(trifluoromethanesulfonyl)benzene (Step 4), 3.0 g (18 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) and 7.4 g (54 mmol) of anhydrous K2CO3 powder in 90 mL of toluene. The reaction was stirred at reflux for 48 hours, and diluted with CH2Cl2. The resulting solution was washed with water and brine, and dried over MgSO4. Purification by silica gel plug with ethyl acetate/hexane (5:95 to 30:70) gave 4.8 g (56%) of 1,2-dichloro-4-[4-(methylthio)phenyl]-5-(trifluoromethanesulfonyl)benzene as a colorless solid: NMR (CDCl3) δ 2.54 (s, 3H), 7.33 (s, 4H), 7.50 (S, 1H), 7.56 (S, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:20])([F:19])[CH2:17][OH:18]>CCN(CC)CC>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml NEt3 and 25 ml 2,2,2-trifluoro-ethanol was heated to 120° C. for 16 h in a sealed tube. The volatiles were removed under vacuum and the residue was taken up in 70 ml 1N HCl. Extraction with ethyl acetate drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound. MS (m/e): 297.0 (M−H, 100%)