Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>CC#N.CCOC(C)=O.CCOCC>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH:16]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccnc1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reaction time: 1 h

Procedure:
Methyl 2-(chlorosulfonyl)benzoate (14.1 g, 60.0 mmol) was added to a stirred solution of 3-pyridinamine (15.0 g, 159.4 mmol) in CH3CN (0.4 M). The temperature rose to 25° C. and a small amount of reddish oil separated out. CHCl3 (2.0 M, protected with amylenes) was added to return all materials to solution. After 1 h, the solvents were evaporated and the residual oil was partitioned between EtOAc and water. The organic layer was washed with water and was evaporated to give the crude product. The crude product was dissolved in the minimum amount of hot EtOAc and was diluted with ether. The product rapidly crystallized out and after 1 hour filtered off and washed with ether to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H) 8.31 (d, 2H) 7.93 (d, 2H) 7.80 (d, 2H) 7.76 (t, 1H) 7.64 (t, 1H) 7.53 (t, 1H) 7.25 (m, 1H) 4.12 (s, 3H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl>[Sn](F)F.C1(C)C(C)=CC=CC=1>[CH2:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][CH2:7][CH:9]1[O:11][CH2:10]1)[CH:9]1[O:11][CH2:10]1
Reactant: ClCC1CO1
Reactant: OCCCCO
Agent: F[Sn]F
Solvent: Cc1ccccc1C
Product: C(CCOCC1CO1)COCC1CO1
Temperature: 130 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A reactor equipped with stirrer, reflux condenser, dropping funnel and thermometer is charged with 180.24 g (2.0 mol) of 1,4-butanediol and 6.27 g (0.04 mol) of tin difluoride and the charge is heated to 130° C. Then, with efficient stirring, 388.6 g (4.20 mol) of epichlorohydrin are added over 2 hours at a temperature of 130°-140° C., the reaction being initially exothermic. After 3 hours at this temperature, the reaction mixture is cooled to 50° C. and to the turbid solution are added 350 ml of xylene, followed by the addition of 30 g of Prolit Rapid® (filter aid). After stirring for 15 minutes, the suspension is filtered and the filtrate is freed from solvent on a rotary evaporator. Analysis of the tin content of the residual liquid chlorohydrin ether shows that this ether still contains only about 13% of the total amount of tin catalyst, i.e. 87% of the catalyst can be separated by filtration. The liquid chlorohydrin ether (589 g) is heated to 55° C. and 336 g (4.2 mol) of a 50% aqueous solution of sodium hydroxide are added dropwise at this temperature, with efficient stirring, over 30 minutes. After stirring for 2.5 hours at 50°-60° C. and cooling to room temperature, the suspension is filtered and the filtrate washed with xylene. The organic phase of the two-phase clear filtrate is dried over magnesium sulfate and filtered, and the filtrate is freed from solvent on a rotary evaporator under vacuum (bath temperature 50° C.). Yield: 343 g (85% of theory) of colourless 1,4-butanediol diglycidyl ether for which the following analytical values are obtained: epoxy value: 7.81 eq/kg; total chlorine content: 5.5%; hydrolysable chlorine content: 131 ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:18]([CH2:19][N:20]([CH3:22])[CH3:21])=[N:17][C:16]([C:23]([OH:25])=[O:24])=[N:15]1)=[O:6].[CH3:30]O>>[CH3:30][O:24][C:23]([C:16]1[N:17]=[C:18]([CH2:19][N:20]([CH3:22])[CH3:21])[N:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=2[Cl:2])[N:15]=1)=[O:25]
Reactant: CN(C)Cc1nc(C(=O)O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
For conversion into the methyl ester already mentioned, 10 ml of a 6 N solution of hydrogen chloride in methanol is added to a solution of 2.08 g (0.005 mole) of crude 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylamino-methyl)-1H-1,2,4-triazole-3-carboxylic acid in 30 ml of methanol, and the whole is refluxed for 16 hours. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice-cold 1 N sodium bicarbonate solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue crystallises out on trituration with ether. After filtration with suction and drying in vacuo, there is obtained pure 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylamino-methyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 133°-135°.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH2:2][C:3]4[CH:16]=[N:15][C:6]5[C:7]6[N:8]([CH:12]=[CH:13][CH:14]=6)[C:9](=[O:11])[NH:10][C:5]=5[CH:4]=4)[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)[CH2:19][CH2:18]1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (25 mg, 0.116 mmol), N-cyclopropyl-4-(piperazin-1-yl)benzamide (35.6 mg, 0.145 mmol) and (cyanomethyl)trimethylphosphonium iodide (45.2 mg, 0.186 mmol) in Propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.101 mL, 0.581 mmol) at 23° C. The reaction was stirred at 95° C. for 6 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-cyclopropyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0355 g, 0.080 mmol, 69.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.47-0.59 (m, 2 H) 0.59-0.70 (m, 2 H) 2.52-2.59 (m, 4 H) 2.79 (tq, J=7.36, 3.94 Hz, 1 H) 3.19-3.31 (m, 4 H) 3.62 (s, 2 H) 6.70-6.78 (m, 1 H) 6.93 (d, J=9.09 Hz, 2 H) 7.07 (dd, J=3.66, 1.64 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.66-7.68 (m, 1 H) 7.68-7.73 (m, 2 H) 8.14 (d, J=4.29 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.62 (br. s., 1 H). ESI-MS: m/z 443.4 (M+H)+. mp=269.9-271.7° C.
Reaction SMILES: [C:1]1([C:7]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[C:15]4=[C:16](C5C=CC=CC=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[C:18](B(O)O)[CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:40]=[C:39]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:66][CH2:65]OCC1>C1(C)C=CC=CC=1.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.O>[C:66]1([C:37]2[N:42]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]=[C:39]([C:49]3[CH:54]=[C:53]4[C:52]5=[C:51]([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=6[N:14]5[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:7]4([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:50]=3)[N:38]=2)[CH:65]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: C1COCCO1
Reactant: OB(O)c1cc2c3c(c1)c1ccccc1n3-c1ccccc1C2(c1ccccc1)c1ccccc1
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: Cc1ccccc1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc4c5c(c3)c3ccccc3n5-c3ccccc3C4(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
20 g (44 mmol) of 8,8-diphenyl-8H-indolo[3,2,1-de]acridine-6-boronic acid, 11.7 g (44 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine and 2.9 g (27.4 mmol) of sodium carbonate are suspended in 70 ml of toluene, 70 ml of dioxane and 50 ml of water. 1.44 mg (1.24 mmol) of Pd(PPh3)4 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 22.4 g (35 mmol), corresponding to 80% of theory.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH2:18][NH2:19].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[N:18][NH:19][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NN
Reactant: COC(=O)c1ccccc1CN1CCOCC1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1ccccc1CN1CCOCC1

Procedure:
A solution of N-bromosuccinimide, dibromomethane (3.56 g, 20 mmol) and methyl-2-methylbenzoate (3.04 g, 20 mmol) in 30 mL CHCl3 was refluxed for 4 h. The solvent was evaporated and the residue was purified by column chromatography, with EtOAc:hexanes, 1:5, as eluant, yielding (3.496 g, 76%) of 2-bromomethyl-benzoic acid methyl ester. A solution of 2-bromomethyl-benzoic acid methyl ester (368 mg, 2 mmol) and morpholine (174 mg, 2.0 mmol) in 8 mL DMF with 1 mL HCl (2 N) was refluxed overnight. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc:hexanes, 1:4, yielding (180 mg, 38%) 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester. The title compound was prepared from 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester, hydrazine and then 3-trifluoromethyl-benzaldehyde in two steps by procedures similar to Example 29. 1H NMR (CDCl3): 8.46 (s, 1H), 8.02 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.22 (m, 1H), 3.82 (t, J=4.8 Hz, 4H), 2.64 (t, J=4.8 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[S:18])=[O:15]>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:17](=[S:18])[NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[CH3:11])=[O:5]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Product: Cc1ccccc1C(=O)NC(=S)Nc1ccccc1C(N)=O
Yield: 95.8 %

Procedure:
To a stirred mixture of 4.9 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 6.67 g of 2-methylbenzoyl isothiocyanate in 100 ml of ether over 15 minutes After a few hours, the solid was collected, giving 10.8 g of the desired product as grey crystals, mp 181°-185° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([OH:1])[C:3]=1[F:13]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(F)c(F)c(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A solution of 3-hydroxy-2,4,5-trifluorobenzoic acid (50 g, 0.26 mol) (prepared in an analogous manner to that described in Eur. Pat. Publication 271275) in methylene chloride (500 mL) was added oxalyl chloride (79 g, 0.62 mol). This solution was stirred at room temperature for 18 hours, cooled to 5° C. and then treated dropwise with methanol (100 mL). The mixture was stirred at room temperature for 2 hours, refluxed for 0.5 hour, cooled and concentrated. The residue was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated to provide 16.7 g of the desired 3-hydroxy-2,4,5-trifluorobenzoic acid methyl ester. Acidification of the bicarbonate layer, extraction with ether and concentration provided an additional 37 g of desired product as indicated by NMR, This material was not purified further but carried into the next step.
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(O)C>[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:3]([CH3:4])[CH2:2][C:1]#[N:5])[CH2:15][CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C/C=C/C#N
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(CC#N)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
(E)-but-2-enenitrile (4.5 ml, 55.0 mmol) and triethylamine (2 drops) were added sequentially to a solution of piperidin-4-yl-carbamic acid tert-butyl ester (10 g, 50.0 mmol) in ethanol (120 ml) at 25° C. The reaction mixture was stirred at 60° C. for 1 week, then was cooled to 25° C. and concentrated under reduced pressure to afford crude [1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as tan oil. 1H NMR (400 MHz, CDCl3) δ 4.48 (s, 1H), 3.42 (s, 1H), 3.09-2.95 (m, 1H), 2.81-2.61 (m, 3H), 2.49 (dd, J=16.7, 6.0 Hz, 2H), 2.39-2.23 (m, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.44 (s, 9H), 1.18 (d, J=6.7 Hz, 3H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[CH3:26]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2C)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 4-fluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2-methyl-phenol (230 mg, 0.65 mmol, 1.0 eq) in DMF (5 mL) was added Cs2CO3 (420 mg, 1.3 mmol, 2.0 eq) and isopropyl 2-bromoacetate (140 mg, 0.78 mmol, 1.2 eq). The reaction was stirred at room temperature for 1 h then water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 400:1 to 40:7) to give the title compound as a colorless oil (180 mg, 62%).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].IC.[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:23])[C:19]=3[NH:20]2)=[CH:12][CH:11]=1>CN(C=O)C.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:23])[C:19]=3[N:20]2[CH3:1])=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2c1[nH]c1cc(Br)ccc21
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)CCCC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Cs2CO3 (2.5 g, 7.5 mmol) and iodomethane (0.47 mL, 7.5 mmol) were added to a solution of 7-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.7 g, 6.3 mmol) in DMF (21 mL), and the resulting mixture was stirred for 4 h at ambient temperature. The reaction was diluted with H2O (25 mL), and the resulting solution was stirred for 15 minutes. The resulting precipitate was collected by filtration, washed with H2O (200 mL) and dried to yield the title compound (1.5 g, 87%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=1.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.25 (dd, J=8.5, 1.5 Hz, 1H), 3.98 (s, 3H), 2.96 (t, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 2.13-2.10 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].O.O.[C:14]1([S:20]([O-:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].O>CS(C)=O>[C:14]1([S:20]([CH2:2][C:3]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)OC1CCCCC1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CS(=O)(=O)c1ccccc1)OC1CCCCC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
To a solution of cyclohexyl bromoacetate (15.6 g, 0.0705 mole) in dimethylsulfoxide (120 ml), sodium benzenesulfinate dihydrate (15 g, 0.075 mole) was added in a small portion at 20°-40° C., and reacted with stirring at 60° C. for 6 hours. After cooling, the reaction mixture was poured into cold H2O (1.5 liter). The precipitate was filtered, washed with H2O and dried to give 15.3 g of cyclohexyl benzenesulfonylacetate as a white crystals having a melting point of 35°-38° C.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC.[CH2:20](O)[CH3:21]>>[CH2:20]([S:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:21]
Reactant: CCO
Reactant: Sc1ccc2ccccc2c1
Agent: CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSc1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a solution, stirred under an inert atmosphere at ambient temperature, of 40 g of 2-mercapto naphthalene in 1 liter of anhydrous ethanol, there are slowly added 24.4 g of potash. The addition being completed, stirring is maintained for 2 hours, then there is slowly added a solution of 21 cm3 of bromomethane dissolved in 100 cm3 of anhydrous ethanol. After 3 hours of stirring, the reaction mixture is left overnight, then filtered and the filtrate is concentrated under a vacuum. The resulting crude product is stirred in 800 cm3 of water, then extracted 4 times with 150 cm3 of dichloromethane. The dichloromethane phases are combined, washed with a saturated solution of ammonium chloride, then dried on magnesium sulfate. The solvent is rectified under vacuum and 38 g of 2-ethylthio naphthalene are obtained and used as such for the following reactions.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([NH:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986) (197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated with excess triethylamine at 0° C. followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0-10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7](F)[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: C[O-]
Reactant: Nc1nc(F)c(OC(F)F)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At -10° to 0° C. and over a period of 15 minutes, 26.1 g (0.145 mol) of 30% strength sodium methylate was added, while stirring, to 31.0 g (0.145 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoropyrimidine in 300 ml of methanol. The mixture was stirred for 30 minutes at 0° C. and for 1 hour at 25° C. The reaction mixture was evaporated down under reduced pressure and worked up as above. There was obtained 31.6 g (96.6% of theory) of the title compound as a colorless oil; nD22 =1.5039.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=O)[O:7]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([NH2:37])=[CH:32][C:31]=1[NH2:38]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:7])[NH:37][C:33]1[CH:32]=[C:31]([NH2:38])[C:30]([F:29])=[CH:35][C:34]=1[CH3:36]
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(F)c(N)cc1N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c(N)cc1NC(=O)OCC[Si](C)(C)C
Temperature: 50 °C
Yield: 28 %

Procedure:
Example 48(a) was prepared in a similar manner as Example 41(a) from the starting material described below. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, 1H, J=4.8 Hz), 7.95 (d, 1H, J=9.49 Hz), 7.84 (td, 1H, 1=7.71 Hz, =1.78 Hz), 7.70 (d, 1H, J=7.95 Hz), 7.53 (d, 1H, J=16.59 Hz), 7.40 (d, 1H, J=7.92 Hz), 7.29 (qd, 1H, 1=7.45 Hz, J=1.07 Hz), 7.11 (d, 1H, 1=11.8), 7.03-7.06 (m, 2H), 6.71 (s, 1H), 4.50 (q, 2H, J=7.16 Hz), 2.27 (s, 3H), 2.26 (s, 3H), 1.38 (t, 3H, 1=7.11 Hz). MS (ESI+) [M+H]/z Calc'd 496, found 496. Anal. Calc'd: C, 67.86; H, 5.29; N, 19.79. Found: C, 66.24; H, 5.50; N, 18.61. The starting material was prepared as follows: A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5 mmol) and 10% Pd/C (200 mg) in MEOH (20 ml) was hydrogenated at 23° C. for 24 h. The reaction mixture was filtered through celite and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate-hexane) gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg, 87%). To a solution of carbonic acid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (566 mg, 2 mmol) in DMF (4 ml) at 23° C. under an atmosphere of argon was added DMAP (12 mg. 0.1 mmol), DIEA (0.35 ml, 2 mmol) and 4-fluoro-6-methyl-benzene-1,3-diamine. The resulting solution was heated to 50° C. for 48 h. The reaction mixture was quenched with saturated NaHCO3 (aq), extracted with EtOAc (3×20 ml). The EtOAc was removed in-vacuo, and the residue was re-dissolved in Et2O then washed with 3 N NaOH (aq), water, brine, dried with Na2SO4, filtered and concentrated. Purification by silica gel chromatography (2:8-7:3 ethyl acetate-hexane) gave (5-amino-4-fluoro-2-methyl-phenyl)carbamic acid 2-trimethylsilanyl-ethyl ester (160 mg, 28%). MS (ESI+) [M+H]/z Calc'd 634, found 634.