Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12](=[O:26])[CH2:13][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:15])[CH3:11])=[CH:6][CH:5]=1.CO>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[N:14]([CH2:13][C:12](=[O:26])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)[CH3:11])[CH3:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(=O)N(C)c1ccc(CO)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Under argon 742.7 mg (32.4 mmol, 1.5 eq) lithium borhydride in 35 ml THF were added dropwise to 8 g (21.6 mmol) 4-[[(Benzyloxycarbonyl-methyl-amino)-acetyl]-methyl-amino]-benzoic acid methyl ester in 100 ml THF at RT. The suspension was stirred at RT over night, heated to 50° C. for 3.25 h, recooled to RT and 21 ml MeOH were added slowly. The solution was added to ice water, extracted with ether (3×), the combined organic layers were washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with a gradient of CH2Cl2/MeOH (100:0-99.9:0.1) yielding 3.9 g (52%) {[(4-Hydroxymethyl-phenyl)-methyl-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester as yellow oil (Rf 0.4 CH2Cl2:MeOH 9:1), MS: 343 (MH+).
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1.[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>O1CCCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[N:13][N:14]2[CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])=[CH:10][CH:9]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1n[nH]c2cc(Br)ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(S(=O)(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
Sodium tert-butoxide (0.035 g) was added to an ice-cold solution of 6-bromo-3-[(4-fluorophenyl)sulfonyl]-1H-indazole (Intermediate 69) (0.11 g) in tetrahydrofuran (1.5 ml). 2-(Trimethylsilyl)ethoxymethyl chloride (0.06 ml) was then added and the mixture was warmed to room temp. over 1 h. The reaction was quenched using 2M aqueous ammonia (1 ml) and methanol (1 ml) the solvent was evaporated and the residue was purified on a Varian Bond-Elut SPE cartridge, eluting with cyclohexane:dichloromethane (100:0 to 0: 100) to give the title compound (0.67 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[N:4][N:3]=1.[OH-].[Na+]>CN1CCCC1=O>[C:6]1([C@H:5]([NH:4][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[N:4][N:3]=2)[CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Clc1nnc(-c2ccsc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2ccsc2)c2ccccc12)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 143.6 %

Procedure:
510 mg of 1-chloro-4-(3-thienyl)phthalazine and 790 mg of D-α-phenylethylamine were dissolved in 2 ml of N-methylpyrrolidone, and the solution was stirred at 140° C. for 6 hours. After cooling the solution, an aqueous 5% NaOH solution was added to the solution, and the resultant solution was extracted with chloroform. The organic layer was dried, concentrated, purified by silica gel chromatography (eluent: hexane, chloroform, ethyl acetate), and recrystallized from ether to obtain 492 mg of (R)-1-(α-phenylethylamino) -4-(3-thienyl)phthalazine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Product: COc1ccc(CN(Cc2ccc(OC)c([N+](=O)[O-])c2)c2ccc(F)cc2)cc1[N+](=O)[O-]
Yield: 91 %

Procedure:
4-Fluoroaniline and 4-methoxy-3-nitrobenzyl bromide were processed using the method described in Example 1A to provide 2.33 g (91%) of the title compound. MS (ESI; M+H) m/z=442.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[OH:23][C:21]1[CH:22]=[C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:18]=[CH:19][C:20]=1[CH3:24]
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: COc1ccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2c1

Procedure:
To a suspension of 200 mg (0.91 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile and 135.5 mg (1.10 mmol) of 5-amino-o-cresol in 10 mL of 2-ethoxy ethanol was added 105.6 mg (0.91 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr, and then the solvent was removed to give a residue. To the residue was added about 30 mL of water and neutralized to pH 7-8 by addition of diluted sodium carbonate solution. The precipitate was collected by filtration and washed with water and ether. After drying in vacuo, this afforded 277 mg (99%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 305.9.
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1>[O-2].[O-2].[Mn+4].ClCCl>[OH:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH:11]=[O:12])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1
Reactant: CSc1ncc(CO)c(NC[C@H](C)O)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ncc(C=O)c(NC[C@H](C)O)n1
Yield: 72.6 %

Procedure:
4-((S)-2-hydroxy-propylamino)-2-methylsulfanyl pyrimidine-5-methanol (26 g, 100 mmol) and 1 L of dichloromethane were combined with stirring and treated with manganese dioxide (102 g, 1 mol). The resulting suspension was stirred for 24 hours and then filtered through celite. The filter residue was washed with dichloromethane (100 mL) and the combined filtrate and washings were evaporated under reduced pressure to give 16.5 g of the 4-((S)-2-hydroxy-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cn(CC2CCCCC2)c2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(CC3CCCCC3)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1-cyclohexylmethyl-1 H-indol-3-yl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-cyclohexylmethyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27](O)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.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.[F:67][C:68]([F:78])([F:77])[CH2:69][CH2:70][N:71]1[C:75](=[O:76])[CH2:74][NH:73][CH2:72]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([N:73]4[CH2:74][C:75](=[O:76])[N:71]([CH2:70][CH2:69][C:68]([F:67])([F:77])[F:78])[CH2:72]4)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: O=C1CNCN1CCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)c3ccccc23)CN1CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (10 mL), 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalene-1-carboxylic acid (70 mg, 0.14 mmol, 1.00 equiv), HATU (74 mg, 0.19 mmol, 4.00 equiv), DIEA (218 mg, 1.69 mmol, 4.00 equiv), 3-(3,3,3-trifluoropropyl)imidazolidin-4-one (31 mg, 0.17 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC. This resulted in 32 mg (34%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalen-1-yl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light brown solid. (ES, m/z): 693 [M+41]+; (300 MHz, CD3OD, ppm): δ 8.98-8.95 (m, 1H), 8.04-7.96 (m, 3H), 7.92-7.85 (m, 2H), 7.74-7.65 (m, 3H), 5.26 (s, 1H), 4.88-4.52 (m, 2H), 4.36-4.29 (m, 2H), 3.82 (s, 1H), 3.73 (t, J=6.6 Hz, 1H), 3.50 (t, J=7.5 Hz, 1H), 2.68-2.60 (m, 1H), 2.43-2.37 (m, 1H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:15])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=CC(=O)O
Reactant: CCCCCCCC(C)=O
Agent: O=P(O)(O)O
Product: CCCCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (5.35 g, 7.0 mmol), 2-nonanone (14.2 g, 1.0 mol) and orthophosphoric acid (20 ml). νmax 2925, 2850, 1700, 1450, 1410, 1350, 1220, 1120, 870, 770, 720 cm−1. 1H n.m.r. δ (CDCl3) 0.87, t J 7.2 Hz, 3H, CH3; 1.29, m, 8H, CH2; 2.39, s, 3H, CH3; 2.77, t J 6.8 Hz, 2H, CH2; 6.50, s, CH.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[S:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:34]1[CH:35]=[CH:36][S:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccsc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. thiophene-3-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)thiophene-3-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.Cl.[CH3:10][O:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:23])=[NH:20])=[CH:14][CH:13]=1>C(O)C>[ClH:7].[CH3:3][C:4]1([CH3:6])[N:20]=[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:35][CH:34]=2)[NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:23]1
Reactant: CCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccc(OC)cc2)N1

Procedure:
100 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 2.0 g (4.6 mmol) of N1-(4-methoxyphenethyl)-N5-nonyl-biguanide dihydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure to give a residue, which was dissolved in hydrous ethanol. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7)) to obtain 1.2 g of a colorless resinous solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Chlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.23 (t, 1H), 7.19 (s, 1H), 6.90 (d, 1H), 6.79 (d, 1H), 5.37 (s, 2H), 3.58 (m, 4H), 3.29 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=421.1, found=421.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[C:3]=1[F:11].[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([O:8][CH3:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(F)c(F)c1F
Solvent: O
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc(F)c(F)c1F
Temperature: 60 °C

Procedure:
To a solution of 1,2,3-trifluoro-4-methoxybenzene (1.6 g, 10 mmol) in acetic acid (20 mL) was added nitric acid (5 mL) and the mixture was heated at 60° C. for 3 hours. After cooling to ambient temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were concentrated to give the crude title compound, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15](CN(C)C)=[C:14](CN(C)C)[N:13]=[C:12]1[S:24]CCC(OCC)=O.[O-]CC.[Na+].[Na]>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([N:11]([CH3:15])[CH3:2])=[C:14]([N:13]([CH3:14])[CH3:12])[NH:13][C:12]1=[S:24]
Reactant: CCOC(=O)CCSc1nc(CN(C)C)c(CN(C)C)n1C1CCc2ccccc2C1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CN(C)c1[nH]c(=S)n(C2CCc3ccccc3C2)c1N(C)C
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 116.7 %

Procedure:
A mixture of ethyl 3-[1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylaminomethyl) imidazol-2-ylthio]propionate (0.55 g, 1.2 mmol) and sodium ethoxide (3.5 mL of a solution prepared from 450 mg sodium in 45 mL of ethanol, 1.4 mmol) in 5 mL of ethanol was stirred at approximately 25° C. for 1.75 hours. The mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried (K2CO3), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (97:3) to give 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di (dimethylamino)-1,3-dihydroimidazole-2-thione (0.24 g, 0.7 mmol), m.p. 182°-184° C.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:16][CH2:15][CH2:14][S:13]2)[N:7]=1.[CH3:17][N:18]=[C:19]=[S:20].C>CCCCCC.C(O)C.C(OCC)(=O)C.O.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:17][NH:18][C:19]([C:12]1([C:8]2[N:7]=[N:6][CH:11]=[CH:10][CH:9]=2)[CH2:16][CH2:15][CH2:14][S:13]1)=[S:20]
Reactant: CN=C=S
Reactant: c1cnnc(C2CCCS2)c1
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=S)C1(c2cccnn2)CCCS1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.7 %

Procedure:
A mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 36 cc) is added dropwise and in the course of 15 minutes to a 1.6 M solution of n-butyllithium in hexane (55 cc), kept under a nitrogen atmosphere and at a temperature of about -60° C. A solution of 2-(pyridazin-3-yl)-tetrahydrothiophen (9.7 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 36 cc) is then added in the course of 20 minutes. After stirring for 15 minutes at the same temperature, a solution of methyl isothiocyanate (6.4 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 36 cc) is added in the course of 15 minutes. The reaction mixture is subsequently stirred for 1 hour at -65° C. and then for one hour whilst allowing the temperature to rise gradually to -10° C. It is then run into a mixture of distilled water (350 cc) and ethyl acetate (300 cc). After decantation, the aqueous solution is extracted with ethyl acetate (200 cc). The organic extracts are combined, washed three times with distilled water (900 cc in total), dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 55° C. The product obtained (12.4 g) is combined with a product (1 g) prepared under the same conditions, and the combined product is chromatographed on neutral silica gel (154 g) contained in a column of diameter 3.2 cm. The column is eluted with a cyclohexane/ethyl acetate mixture (90/10 by volume; 500 cc), a cyclohexane/ethyl acetate mixture (80/20 by volume; 1000 cc), a cyclohexane/ethyl acetate mixture (70/30 by volume; 2250 cc) and a cyclohexane/ethyl acetate mixture (50/50 by volume; 2500 cc), 250 cc fractions being collected. Fractions 19 to 25 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 55° C. The product obtained (2.4 g) is dissolved in boiling ethanol (50 cc); decolourising charcoal (0.15 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 30 minutes at 0° C. The resulting crystals are filtered off, washed with ethanol (2 cc) and then twice with diisopropyl ether (6 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. N-Methyl-2-(pyridazin-3-yl)-tetrahydrothiophen-2-carbothioamide (0.8 g), melting at 199° C., is thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:17].N1C=CN=C1.[CH:25]([Si:28](Cl)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>CN(C)C=O>[CH3:26][CH:25]([Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:17])[CH3:27]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1Nc2ccccc2C12COc1cc(O)ccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2c(c1)OCC21C(=O)Nc2ccccc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.0 g, 11.8 mmol) in anhydrous N,N-dimethylformamide (30 mL) under nitrogen were added imidazole (1.97 g, 28.9 mmol) and triisopropylsilyl chloride (6.03 mL, 28.5 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo to dryness. The residue was extracted with ethyl acetate (2×50 mL), the combined organic solution was dried over sodium sulfate, and filtered. The filtrate was concentrated and purified by flash chromatography with 30% ethyl acetate in hexanes to afford 6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.68 g, 69% yield) as colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.48-8.08 (br, 1H), 7.29-6.90 (m, 4H), 6.10 (d, J=8.1 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.35 (dd, J=8.1, 2.1 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 1.34-0.98 (m, 21H).
Reaction SMILES: N=C=N.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:16]=1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=S.CS(Cl)(=O)=O.C(N(CC)CC)C>>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[N:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:16]=1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: Cc1ccccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Product: Cc1ccccc1N=C=Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Yield: 104.1 %

Procedure:
Following the general procedure for carbodiimide formation outlined in example 12, N-(2-methylphenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]thiourea (410 mg, 0.8 mmol), methanesulfonyl chloride (0.14 mL, 1.6 mmol) and triethylamine (0.23 mL, 1.6 mmol) were reacted to form the desired product (400 mg, crude). 1H NMR (CDCl3) δ 0.39 (s, 6H), 1.05 (s, 9H), 1.72 (m, 4H), 2.37 (s, 3H), 2.87 (s, 6H), 7.04 (d, 1H), 7.18 (m, 4H), 7.29 (d, 1H).