Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[CH:11][CH:10]=1.N1C=CC=CC=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([Cl:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[ClH:36].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([N:5]3[CH2:4][CH:3]4[CH2:8][CH:6]3[CH2:7][N:2]4[CH3:1])=[CH:10][CH:11]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC2CC1CN2c1ccc(N)c2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CC4CC3CN4C)c3ccccc23)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)-1-naphthylamine (0.210 g, 0.829 mmol) (prepared according to methods A and B), pyridine (468 μL, 5.80 mmol) in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.158 g, 0.829 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and then concentrated. The crude product was purified via column chromatography (SiO2, CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give the pure base which was converted to its HCl-salt: yield 160 mg (43%); 1H NMR (DMSO-d6) δ 10.78 (br s, 1H), 9.90-9.88 (m, 1H), 8.02-7.98 (m, 2H), 7.58-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.33-7.30 (m, 2H), 7.06-7.03 (m, 1H), 6.93-6.90 (m, 1H), 4.38-4.30 (m, 3H), 3.65-3.60 (m, 3H), 2.90-2.87 (m, 1H), 2.86-2.83 (m, 3H), 2.36 (br s, 2H), 2.35 (s, 3H); MS (posES-FIA) m/z=407.1655 (M+H) (calc 407.1667).
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(O)=O.[CH:26]1[CH:31]=[C:30]([C:32]([OH:34])=[O:33])[C:29]([SH:35])=[CH:28][CH:27]=1.Cl[C:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)/[C:39](=[N:48]/[S:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)(=[O:51])=[O:50])/[CH:38]=1>>[C:55]1([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:56]=[CH:57][C:52]([S:49]([NH:48][C:39]2[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]([OH:47])=[C:37]([S:35][C:29]3[CH:28]=[CH:27][CH:26]=[CH:31][C:30]=3[C:32]([OH:34])=[O:33])[CH:38]=2)(=[O:51])=[O:50])=[CH:53][CH:54]=1
Reactant: O=C(O)c1ccccc1S
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Agent: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(O)c1ccccc1Sc1cc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2c1O

Procedure:
5.2.62 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)benzoic acid (14t) was prepared according to the procedure of procedure B for 10a except using 2-thiosalicylic acid and (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)biphenyl-4-sulfonamide (12b), which afforded the title compound 17.4 mg (65.9%) as an off-white solid, m.p.: 205° C. (dec.).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(CCCCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCCCC=O)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
A solution of DMSO (9.36 g, 120 mmol) in 20 mL of CH2Cl2 was added dropwise over 10 minutes to a solution of oxalyl chloride (10.16 g, 80 mmol) in CH2Cl2 (80 mL) at -70° C. under an atmosphere of nitrogen. After stirring for 15 minutes at -70° C., a solution of the product of step B (7.56 g, 40.0 mmol) in CH2Cl2 (50 mL) was added dropwise over 10 minutes and the solution was stirred at -70° C. for 15 minutes. Neat triethylamine (24.2 g, 240 mmol) was added rapidly, the ice bath was removed and the mixture allowed to warm to ambient temperature over 30 minutes. The reaction mixture was diluted with CH2Cl2 (100 mL), washed successively with water, 1N NaHSO4 and brine, dried (MgSO4), filtered through a pad of silica gel and eluted with CH2Cl2. The solvent was evaporated under reduced pressure affording 7.23 g of title product (97%) as a thick oil of sufficient purity to be used in the next reaction. 1H-NMR (300 MHz, CDCl3) 61.67 (m, 4H), 2.47 (m, 2H), 2.70 (m, 2H), 7.37 (d, J=8HZ, 2H), 7.48 (d, J=8Hz, 2H), 9.77 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:47]1([CH:53]2[CH2:57][CH2:56][NH:55][CH2:54]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:55]1[CH2:56][CH2:57][CH:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:54]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(c2ccccc2)C1
Reaction time: 2 h
Yield: 18.1 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidine (7 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1524.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH:11]=[CH:12]N(C)C)=[CH:6][CH:5]=1.Cl.[NH2:19][C:20]([NH2:22])=N.[OH-:23].[Na+]>CO>[OH:23][C:20]1[N:22]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=2)[CH:11]=[CH:12][N:19]=1
Reactant: N=C(N)N
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C(=O)C=CN(C)C)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccnc(O)n2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of 4-(3-Dimethylamino-acryloyl)-benzoic acid methyl ester (1 g, 4.29 mmol; Prepared according to the method reported by S. Murahashi et al. Bulletin of the Chemical Society of Japan, 1987, 60, 3285) in MeOH (8.5 mL) is added guanidine hydrochloride (1.23 g, 12.86 mmol) and NaOH (412 mg, 10.3 mmol). The mixture is stirred at 80° C. for 24 h and then cooled down to room temperature. The mixture is concentrated and treated with H2SO4/H2O (1:1, 20 mL) and heated to 120° C. for 14 h. After cooling down to room temperature, the mixture is basified by pouring into ice cold NH4OH (50 mL) and acidified to pH= 1 by adding concentrated hydrogen chloride solution. The precipitate is collected by filtration, washed with acetonitrile and dried in a vacuum oven for 24 h to yield 680 mg of crude 4-(2-hydroxy-pyrimidin-4-yl)-benzoic acid.
Reaction SMILES: [Na].[F:2][C:3]([F:7])([F:6])[CH2:4][OH:5].[F:8][C:9]([F:29])([F:28])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH:20]3[CH2:22][C:23]4([CH2:26][CH:19]3[C:18]2=[O:27])[CH2:25][O:24]4)=[CH:13][CH:12]=1>O>[OH:24][C:23]1([CH2:25][O:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH2:26][CH:19]2[C:18](=[O:27])[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][C:9]([F:8])([F:28])[F:29])=[CH:16][CH:15]=3)[CH2:21][CH:20]2[CH2:22]1
Reactant: OCC(F)(F)F
Reactant: O=C1C2CC3(CO3)CC2CN1c1ccc(OC(F)(F)F)cc1
Agent: [Na]
Solvent: O
Product: O=C1C2CC(O)(COCC(F)(F)F)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A small piece of sodium was added to 2,2,2-Trifluoro-ethanol (20 mL), and the mixture was stirred at 80° C. for 5 minutes, then rac-(3aR,5S,6aS)-2-[4-(trifluoromethoxy)phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxiran]-1-one was added. The mixture was stirred for 6 h. The solution was then poured into water (25 mL) and extracted with ether (3×20 mL), dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to yield the title compound. 1H NMR (300 MHz, CDCl3): δ 7.66-7.63 (m, 2H), 7.20-7.17 (m, 2H), 4.13 (t, 1H, J=9.6 Hz), 3.86 (q, 2H, J=8.7 Hz), 3.71-3.61 (m, 3H), 3.22-3.17 (m, 1H), 3.05-2.99 (m, 1H), 2.38-2.33 (m, 1H), 2.09-1.76 (m, 4H); LC-MS: 414.1 [M+1]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.[CH:27](OCC)=[O:28]>C1COCC1>[Br:19][C:20]1[CH:25]=[N:24][C:23]([F:26])=[C:22]([CH:21]=1)[CH:27]=[O:28]
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cnc1F
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
To a solution of diisopropylamine (17 mL, 0.17 mol) in dry THF (200 mL) was added 2.5 M n-BuLi in hexane (68 mL, 0.17 mol) dropwise at 0° C. under N2 atmosphere. After the addition, the resulting mixture was cooled to −65° C. A solution of 5-bromo-2-fluoropyridine (25 g, 0.14 mol) in dry THF (100 mL) was then added dropwise. The resulting mixture was stirred at −65° C. for 90 minutes. Then ethyl formate (15.6 g, 0.21 mol) was added dropwise to the mixture. After stirred for 10 minutes, the reaction mixture was quenched with a solution of 10% citric acid in THF (100 mL) at −65° C. The resulting mixture was warmed up to room temperature, poured into water (100 mL) and extracted with EtOAc (200 mL). The organic layer was separated and washed with saturated aqueous NaCl (100 mL×2), dried over Na2SO4 and concentrated in vacuo to yield compound D-1-2 (25 g, 85%) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11]1[N:12]([S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:13]=[CH:14][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])[CH3:10])=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].O>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH2:8][C@@H:9]([C:11]1[N:12]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](C)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@@H](C)N)cc1
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
To a solution of (R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-1-tosyl-1H-pyrrole-3-carboxylate (702c; 25.11 g, 54.0 mmol) in 120 mL DCM was added TFA (Aldrich; 120 mL, 1621 mmol) slowly in portions (Caution: gas evolution was observed). After complete addition, the dark brown reaction was stirred 5 min, was fitted with a water-cooled reflux condenser and drying tube and was placed in a pre-heated 50° C. oil bath. The reaction was heated at reflux for 3 h; gas evolution was mild. The reaction was cooled and concentrated in vacuo and the solid material was dried in vacuo for 48 h to give (R)-2-(1-aminoethyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (22.83 g, 54.1 mmol, 100% yield). 1H NMR (400 MHz, MeOH-d4) d ppm 7.89 (2H, d, J=8.4 Hz), 7.57 (1H, d, J=3.5 Hz), 7.52 (2H, d, J=8.2 Hz), 6.79 (1H, d, J=3.5 Hz), 5.28 (1H, q, J=6.8 Hz), 2.47 (3H, s), 1.32 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 309.0 (M+H)+.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.[Si:19]([O:26][CH2:27][CH:28]1[CH2:42][C:41]2[C:30](=[CH:31][C:32]3[N+:37]([O-:38])=[N:36][C:35](I)=[N:34][C:33]=3[CH:40]=2)[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>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>[CH2:3]([C:35]1[N:36]=[N+:37]([O-:38])[C:32]2[CH:31]=[C:30]3[C:41]([CH2:42][CH:28]([CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:29]3)=[CH:40][C:33]=2[N:34]=1)[CH:2]=[CH2:1]
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2cc3nc(I)n[n+]([O-])c3cc2C1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: C=CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Yield: 99.1 %

Procedure:
Allyltributyltin (4.35 mL, 14.1 mmol) and Pd(PPh3)4 (0.72 g, 0.64 mmol) were added to a N2-purged, stirred solution of iodide 133 (5.88 g, 12.9 mmol) in DME (80 mL) at 20° C. and the reaction mixture was stirred at reflux temperature under N2 for 8 h. The reaction mixture was cooled and partitioned between EtOAc and brine. The organic layer was separated, dried, and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of EtOAc/pet. ether, to give alkene 137 (4.75 g, 99%) as a yellow solid: mp (EtOAc/pet. ether) 49-52° C.; 1H NMR δ 8.23 (s, 1H, H-9), 7.74 (s, 1H, H-5), 6.17-6.24 (m, 1H, CH), 5.20-5.34 (m, 2H, CH2), 3.75-3.80 (m, 2H, CH2), 3.59-3.67 (m, 2H, CH2O), 3.13-3.25 (m, 2H, CH2), 2.92-3.04 (m, 2H, CH2), 2.72-2.84 (m, 1H, H-7), 0.87 [s, 9H, SiC(CH3)3], 0.04 [s, 6H, Si(CH3)2]; 13C NMR δ 164.1, 154.1, 148.3, 147.6, 133.0, 132.4, 123.0, 118.2, 114.5, 65.4, 42.0, 41.7, 35.8, 35.5, 25.8 (3), 18.3, −5.41 (2); HRMS (FAB+) calcd for C20H30N3O2Si (MH+) m/z 372.2107, found 372.2110. Anal. calcd for C20H29N3O2Si.¼H2O: C, 63.9; H, 7.9; N, 11.2. Found: C, 63.9; H, 7.7; N, 10.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br>O1CCOCC1>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)cc1F
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (2.56 g, 16.6 mmol) in dioxane (4 ml) was added a solution of bromine (2.70 g, 16.9 mmol) in dioxane (15 ml) dropwise, and the mixture was stirred at room temperature for 3 hours. The volatile was evaporated in vacuo, and the residue was used for next reaction without further purification. (2.4 g, 62% yield).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]1.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O.O>CN(C=O)C>[F:28][C:27]([F:30])([F:29])[CH2:26][N:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]1
Reactant: COC(=O)c1c[nH]c2c1CCc1cnccc1-2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of methyl 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylate E1 (0.44 mmol) in dry DMF (5 mL) NaH (0.52 mmol) was added. The reaction mixture was stirred at rt for 2 h. After cooling to 0° C., trifluoroethyl triflate (0.52 mmol) in DMF (5 mL) was added dropwise. The mixture was maintained at rt overnight and then poured into icy water and extracted with DCM. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (eluant: DCM/acetone 9:1) afforded the title compound (65% yield). ESI (+) MS: m/z 311 (MH+). 1H NMR: 2.82 (t, J=7.70, 2H), 2.92 (t, J=7.70, 2H), 3.76 (s, 3H), 5.41 (q, J=8.90, 2H), 7.56 (d, J=5.24, 1H), 7.75 (s, 1H), 8.41 (d, J=5.24, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH3:10][S:11](N)(=[O:13])=[O:12].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: CS(N)(=O)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)NS(C)(=O)=O
Yield: 127.4 %

Procedure:
5.1 ml of hexamethyldisilazane (24.5 mmoles) were added to a refluxing mixture of 3.0 g (31.6 mmoles) of methanesulfonamide, 20 mg (0.11 mmole) of saccharin and 15 ml of toluene while a stream of nitrogen passed over the reaction mixture to expel the ammonia evolved, which was absorbed in water and titrated with 1 N H2SO4. It was found that after refluxing for 20 minutes the calculated amount of ammonia was evolved. The solvent and excess hexamethyldisilazane were evaporated in vacuo and the solid residue was vacuum dried to obtain 5.22 g (99.5%) of N-trimethylsilylmethanesulfonamide melting at 69°-74.5° C. The experiment was repeated without the addition of saccharin and the calculated amount of ammonia was evolved in 35 minutes. Workup as described above yielded 5.25 g (100%) of N-trimethylsilylmethansulfonamide melting at 68°-72.5° C.
Reaction SMILES: [CH2:1]1[S:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].[C:9](=O)=O.Cl>C=O.C(O)=O>[CH3:9][N:3]1[CH:2]([C:6]([OH:8])=[O:7])[CH2:1][S:5][CH2:4]1
Reactant: O=C(O)C1CSCN1
Reactant: O=C=O
Agent: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CSCC1C(=O)O
Temperature: 80 °C

Procedure:
L-thiazolidine-4-carboxylic acid (13.3 g) in a mixture of 37% formaldehyde (22.5 ml) and 96% formic acid (39.3 ml) was heated to 80° C. After one hour CO2 evolution ceased. The heating was continued until most of the solvent was removed. The residue was dissolved in methanol and evaporated on the rotovap three times. One equivalent of concentrated hydrochloric acid was added and the resulting salt crystallized from methanol and ethyl ether. Yield 17.0 g (92%).
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1C=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:5]=1C#N.[CH2:16]([OH:19])[CH2:17]O>O>[NH2:3][C:4]1[CH:5]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:17]=1[C:16]([OH:19])=[O:1]
Reactant: CS(=O)(=O)c1ccc(N)c(C#N)c1
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-methylsulfonyl aniline (1.0 g, 4.9 mmol) in N-methylpyrrolidine (10 mL) was added copper (I) cyanide (4.35 g, 48.6 mmol) under nitrogen. The reaction mixture was stirred at 180° C. for 72 hours, cooled to room temperature, poured to a 1:1 mixture of ammonia and water (200 mL), stirred for 1 hour, and then filtered off. The residue was washed with CH2Cl2 (50 mL) and filtrate was extracted with CH2Cl2 (3×20 mL). The combined organic layers were backwashed with water (50 mL), dried over sodium sulfate, and concentrated to provide crude material, which was purified by flash column chromatography (silica gel; 230-400 mesh; ethyl acetate/hexanes=1:5) to obtain 2-amino-5-methanesulfonyl-benzonitrile as a white solid. Yield: 0.1 g (13%). A suspension of potassium hydroxide (2.05 g, 36.7 mmol) in ethylene glycol (9 mL) was heated to 80° C. KOH was dissolved completely at this stage. 2-Amino-5-methanesulfonyl-benzonitrile (0.900 g, 4.59 mmol) was added to the reaction mixture and the bath temperature was increased to 185° C. and stirred for 16 hours. The resultant reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with CH2Cl2 (3×30 mL). The aqueous layer was acidified with 2 N HCl to pH 4-5, extracted with EtOAc (3×30 mL), and the combined organic layers were backwashed with water (30 mL), then brine (30 mL), dried over sodium sulfate, and evaporated, to obtain 2-amino-5-methanesulfonyl-benzoic acid. Yield: 0.750 g (75%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH:29]([C:31]1[N:32]([CH3:44])[CH:33]=[C:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[N:35]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:12]1[C:29]([C:31]2[N:32]([CH3:44])[CH:33]=[C:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[N:35]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by tert-butyl 2-formyl-1-methyl-1H-imidazol-4-ylcarbamate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:17]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCC>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:17]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C@@H:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: CCOC1=N[C@@H]2CCc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CCOC(=O)N[C@@H]1CCc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Temperature: 50 °C
Yield: 70.4 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,4,5,9b-tetrahydronapth[2,1-d]oxazole (1.90 g, 8.76 mmol) in dry toluene (15 ml) was treated with 2-benzylaniline (1.60 g, 8.76 mmol) and a catalytic amount of p-toluenesulfonic acid (0.5 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated at 50° C. for 1.5 h. The reaction was worked up as described in Preparation 5. Trituration with n-pentane afforded the title compound as a pale yellow solid (2.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:36])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:37][CH3:38])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:47]([N:11]1[C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:20]3[C:21](=[O:36])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:23](=[O:24])[C:19]=3[C:18]=2[C:17]2[CH:16]=[C:15]([O:37][CH3:38])[CH:14]=[CH:13][C:12]1=2)[CH:46]=[CH2:45]
Reactant: C=CCBr
Reactant: COc1ccc(CN2C(=O)c3c(-c4ccccc4Cl)cc4[nH]c5ccc(OC)cc5c4c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCn1c2ccc(OC)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)N(Cc1ccc(OC)cc1OC)C3=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To a solution of carbazole (287) (150 mg, 0.28 mmol) prepared as described in example 297 in dimethylformamide (10 mL) under nitrogen was added potassium carbonate (0.39 g, 2.80 mmol) and allyl bromide (720L, 0.84 mmol). The resulting suspension was warmed to 90° C. with stirring for 3 hours before being diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:2), followed by crystallization from diethyl ether/hexane gave carbazole (288) (90 mg, 57%) as a yellow powder, mp 171–173° C. 1H NMR δ [(CD3)2SO] 8.51 (d, J=2.6 Hz, 1H), 7.84 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.58 (m, 1H), 7.53–7.46 (m, 3H), 7.32 (dd, J=8.9, 2.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.45 (dd, J=8.4, 2.4 Hz, 1H), 5.99 (m, 1H), 5.18 (d, J=4.9 Hz, 2H), 5.14 (dd, J=10.3, 1.3 Hz, 1H), 4.99 (dd, J=17.2, 1.3 Hz, 1H), 4.69 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H). Found: C, 69.97; H, 4.75; N, 5.12. C33H27ClN2O5 requires: C, 69.90; H, 4.80; N, 4.94.