Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].C>[I-].[K+].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: NC(=O)COCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: NC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 79.6 %

Procedure:
77 g (0.2685 mole) of levorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example 4.1), 40.5 g (0.2932 mole) of 2-(2-chloroethoxy)acetamide, 62.8 g (0.591 mole) of sodium carbonate and 2 g (0.0120 mole) of potassium iodide are added to 700 ml of toluene. The mixture is heated at reflux temperature for 24 hours. 10 g of Norit are then added and the mixture is filtered while hot through Dicalite. The filtrate is washed with 500 ml of water and then with 500 ml of a saturated aqueous solution of sodium chloride. The organic phase is separated and dried over 250 g of sodium sulfate. It is then filtered and the solvent is evaporated. The residual oil is taken up in 1500 ml of hot diisopropyl oxide. The solution is heated under reflux and allowed to crystallize by cooling in an ice bath. The crystals are filtered, washed with a small amount of diisopropyl oxide and dried under vacuum at 40° C. 82.91 g of levorotatory (-)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide are obtained.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](/[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C.O>C1COCC1>[Br:35][C:32]1[CH:31]=[CH:30][C:29](/[C:22](/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21]/[CH2:20][OH:19])=[CH:34][CH:33]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A 1.2 M solution of DIBAL-H in toluene (45 ml, 42 mmol) was added dropwise, at −15° C. over 20 min, to a stirred solution of (E)-3-(4-bromophenyl)-3-phenylacrylicacid ethyl ester (6.0 g, 18.1 mmol) in dry THF (80 ml), and the mixture stirred for 30 min. Rochelles salt and water was carefully added, and the resulting mixture extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give 5.2 g of (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Li]C(C)(C)C.[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13].[NH4+].[Cl-]>[Cl-].[Cl-].[Zn+2].C1COCC1>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: Cn1cccc1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3cccn3C)c(C)nc12
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A THF solution (10 mL) of N-methylpyrrole (Aldrich, 800 μL, 9.0 mmol) is cooled to −78° C. under N2 then treated with tert-BuLi (1.7 M in pentane, 5.3 mL, 9.0 mmol). The solution is warmed to room temperature for 30 minutes then cooled to −78° C. and treated with ZnCl2 (Aldrich, 0.5 M in THF, 18 mL, 9.0 mmol). The resulting mixture is warmed to room temperature and treated with a THF slurry (5 mL) containing 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.02 gm, 3.0 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 140 mg, 0.17 mmol). The mixture is heated to 60° C. overnight, then poured into sat'd aq NH4Cl (50 mL) and extracted with diethyl ether (75 mL). The organic extract is ished with aq. brine, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to elute the title compound (407.5 mg, 46% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=1[N:1]([S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])[S:21]([C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:23])=[O:22])(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(Cl)ncc1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)c1cc(Cl)ncc1N(S(=O)(=O)c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of 1-(5-amino-2-chloropyridin-4-yl)ethanone (1.0 equiv.) in pyridine (0.26 M) was added 4-nitrophenylsulfonylchloride (3.0 equiv.). The resulting amber solution was stirred at rt for 18 hours, at which time it was poured onto ice. The resulting solid was filtered, rinsed with H2O and pumped on yielding N-(4-acetyl-6-chloropyridin-3-yl)-4-nitro-N-(4-nitrophenylsulfonyl)benzenesulfonamide (88%). LC Rt=4.77 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li][CH3:17]>C(OCC)C.O>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:17])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [Li]C
Reactant: Cc1sc(C(=O)O)cc1-c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cc(-c2ccccc2)c(C)s1
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-4-phenyl-thiophene-2-carboxylic acid (1.50 g, 6.87 mmol) in diethyl ether (100 mL) MeLi (7 mL, 1.5 M in diethyl ether) is added at 5° C. The mixture is stirred at it for 90 min before another portion of MeLi (1 mL) is added. Stirring is continued for 1 h. The mixture is diluted with water and extracted with EA. The organic extracts are evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(5-methyl-4-phenyl-thiophen-2-yl)-ethanone (490 mg) as a colourless oil, LC-MS: tR=1.00 min, [M+1]+=217.10; 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.48-7.33 (m, 5H), 2.54 (s, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]3=[O:32])=[CH:21][CH:22]=2)[CH2:17][O:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH2:15][O:16][CH2:17]3)[C:25]1=[O:32])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc3c(c2)COC3)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc3c(c2)COC3)C1=O
Yield: 35.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(1,3-dihydroisobenzofuran-5-yl)-2-oxopyrrolidine-3-carboxylic acid (0.111 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent 7 to 60% of ethyl acetate in dichloromethane) to give 0.064 g (36%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(1,3-dihydroisobenzofuran-5-yl)-2-oxopyrrolidine-3-carboxamide a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:14](=[O:16])[CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
2-Phenylaniline (5 g, 29.55 mmol) was dissolved in acetic acid (30 mL), acetic anhydride (3.62 g, 35.45 mmol) was added thereto under ice bath, and the mixture was stirred under ice bath for 2 hours. The solution was concentrated under reduced pressure. to the residue was added water (15 mL), and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with purified water, and dried under reduced pressure to obtain 2-phenyl-N-acetylaniline (6.21 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C@H:15]([C:20]([O:22]C(C)(C)C)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C@H:15]([C:20]([OH:22])=[O:21])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNC(=O)OCc1ccccc1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](NCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The product from Example 180A (0.870 mmol) was dissolved in an HCl solution in dioxane (5.0 mL, 4 N), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated to afford the title compound as the hydrochloride salt. The residue was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([OH:18])([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:14]([F:17])([F:16])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: O=C(O)c1cccs1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 3-(Ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:17][N:16]([C:18](=[O:37])[C@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[NH2:29][CH:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:18]([N:16]1[CH2:17][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:15]1)=[O:37]
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CC(OCCCCOCc3ccccc3)(c3ccccc3C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(N)C(=O)N2CC(OCCCCOCc3ccccc3)(c3ccccc3C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
1.14 g (1.89 mmol) of tert-butyl [(R)-2-[3-(4-benzyloxybutoxy)-3-o-tolylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are dissolved in 10 ml of dichloromethane. 3 ml (39 mmol) of trifluoroacetic acid are added dropwise and the mixture is stirred at room temperature for 1 hour and then concentrated to dryness. 1.4 g of 2-amino-1-[3-(4-benzyloxybutoxy)-3-o-tolylazetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are obtained in the form of a colourless resin, in quantitative yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[K+].[Br-]>>[CH:12]([C:10]1[N:11]=[C:4]2[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=[CH:6][N:5]2[CH:9]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1cn2cccc(CO)c2n1
Agent: [Br-]
Agent: [K+]
Product: CC(C)c1cn2cccc(C=O)c2n1
Yield: 57 %

Procedure:
From 3f: reaction time 15 h (yield: 57%); mp 70-72° C.; IR (KBr) 1669, 1540, 1500 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.39 (d, 6H, J=7 Hz), 3.20 (sept, 1H, J=7 Hz), 6.90 (t, 1H, J=7 Hz), 7.46 (s, 1H), 7.77 (d, 1H, J=7 Hz), 8.30 (d, 1H, J=7 Hz), 10.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.4, 28.6, 107.9, 111.2, 123.4, 125.5, 130.2, 143.7, 156.0, 189.2; MS m/z 188 (M+, 60), 173 (56), 160 (100), 145 (26), 78 (21).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:22]1[S:26][C:25]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(#N)C>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:22]3[S:26][C:25]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:24][CH:23]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1)C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 1.70 g. (6.32 mmol.) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 2.30 g. (6.32 mmol.) of dimethyl N-(5-bromothien-2-ylcarbonyl)-L-glutamate, 44 mg. of palladium chloride, 130 mg. of triphenylphosphine, 25 mg. of cuprous iodide, and 1.13 mL. of triethylamine in 30 mL. of acetonitrile was heated at reflux for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue column chromatographed (Waters 500) eluting with 1:19 methanol:methylene chloride to yield dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6yl}ethynyl)thien-2ylcarbonyl]-L-glutamate, m.p. 228°-230° C. Anal. Calc. for C26H27N5O7S: C, 56.41; H, 4.92; N, 12.65; S, 5.79. Found: C, 56.64; H, 4.77; N, 12.88; S, 5.58.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)S(=O)(=O)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)S(=O)(=O)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example I from tert.-butyl 4'-[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2(O)[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:11]([O:19][CH2:20][CH3:21])[CH:10]2[CH3:22])=[C:6]([Cl:24])[CH:5]=[CH:4][N:3]=1.[OH2:25]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([C:8](=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:11]([O:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[C:6]([Cl:24])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC1=C(S(C)(=O)=O)C=CC(O)(Cc2c(Cl)ccnc2Cl)C1C
Reactant: O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(Cl)ccnc2Cl)c1C

Procedure:
To the product of step (a) in 30 ml of toluene was added 4 g manganese dioxide. The suspension was refluxed for 7 hours with mechanical stirring and with azeotropic removal of water. The mixture was filtered and the filter cake washed with ether. The solvent was evaporated in vacuo to yield 2.08 g of 2,4-dichloro-3-(3-ethoxy-2-methyl-4-methylsulfonylbenzoyl)pyridine as a brown semi-solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([OH:32])(=O)=[O:30])[CH:8]=2)[N:3]=1.S(Cl)([Cl:35])=O>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([Cl:35])(=[O:32])=[O:30])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(=O)(=O)O)ccc2n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(=O)(=O)Cl)ccc2n1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
40 ml of thionyl chloride together with one drop of DMF are added to a solution of 5 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzenesulfonic acid. The mixture is stirred at 22° C. for 16 h, evaporated in vacuo, taken up in 500 ml of DCM and extracted twice with 300 ml of water each time. The organic phase is dried over magnesium sulfate, filtered off and evaporated to dryness in vacuo. The residue is employed in the following steps without further purification. Yield: 6.9 g (98%) of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzenesulfonyl chloride;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Si]([C:22]#[N:23])(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(Cl)Cl.C1COCC1.O>[NH2:23][CH2:22][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[OH:9]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc(C(=O)c2ccc(Br)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(O)(CN)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanone (2.06 g, 7.07 mmol), in CH2Cl2 (3.5 mL) at room temperature was added Znl2 (0.15 , 0.47 mmol) followed by addition of TMSCN (4.29 mL, 32.2 mmol). The reaction mixture was stirred at room temperature for 3 h and was quenched by addition of brine (20 mL). The aqueous layer was washed with CH2Cl2 (3×30 mL) and the combined organic extracts were dried over Na2SO4 and concentrated to afford an oil. The resulting oil was dissolved in THF (7 mL) and the solution was added dropwise to a solution of lithium aluminum hydride (LAH) in THF (1M, 8.13 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. To the solution was added H2O (1.5 mL) followed by addition of 15% aqueous sodium hydroxide (NaOH) (1.5 mL) and H2O (4.5 mL). The mixture was filtered trough celite and the celite was washed with EtOAc (20 mL). The filtrate was dried over MgSO4 vand concentrated. Purification by flash chromatography with CH2Cl2/MeOH (20:1) afforded 2.1 g of 2-amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol. 1HNMR (400 MHz, CDCl3) δ 7.44-7.40 (comp, 2H), 7.33-7.26 (comp, 2H), 7.24-7.20 (m, 1H), 7.01-6.99 (m, 1H), 6.97-6.94 (m, 1H), 3.77 (s, 3H), 3.47-3-35 (comp, 2H), 3.29-3.24 (comp, 2H); MS (M+1) 304.1, 306.1.
Reaction SMILES: [Cl-].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]=[CH:10]2)C=CC=CC=1.[CH:29]1([CH2:35][CH2:36][O-:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Na+]>>[NH:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][O:37][CH2:36][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:11]=[CH:10]1
Reactant: CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [O-]CCC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(CCCOCCC2CCCCC2)c[nH]1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propane chloride (see Example 63) and 15 mmol of sodium 2-cyclo-hexylethanolate are treated as described in Example 5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](Cl)=[O:22]>ClCCl.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([Cl:17])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[CH:7]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)ccc1O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
2-Amino-4-chlorophenol (316 mg, 2.2 mmol) and triethylamine (243 mg, 2.4 mmol) were dissolved in dichloromethane (5 mL). A solution of 3,5-dichlorobenzoyl chloride (419 mg, 2 mmol) in dichloromethane (2 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was diluted with ethyl acetate, washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give a light brown solid. The solid was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (205 mg, 32.4%) as a white crystal.
Reaction SMILES: OC(C(F)(F)F)=O.[S:8](=[N:11][CH2:12][C:13]([OH:15])=O)(=[O:10])=[O:9].ON1[C:21]2[N:22]=[CH:23][CH:24]=C[C:20]=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(C(C)C)CC)(C)C>[CH2:21]([N:22]1[CH2:23][CH2:24][S:8](=[O:10])(=[O:9])[NH:11][CH2:12][C:13]1=[O:15])[CH3:20]
Reactant: On1nnc2cccnc21
Reactant: O=C(O)CN=S(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCS(=O)(=O)NCC1=O

Procedure:
To a mixture of the above N-sulfonylglycine TFA salt (0.32 g, 0.98 mmol), 1-hydroxy-7-azabenzotriazole (36 mg, 0.26 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g, 1.13 mmol) in DMF (50 mL), diisopropyl-ethylamine was added dropwise to adjust the pH to 5-6, and the resultant mixture was stirred at room temp overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with chloroform. Collection and concentration of appropriate fractions provided 5-ethyl-1,2,5-thiadiazepan-4-one 1,1-dioxide as white solid.
Reaction SMILES: [N:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:4]1)=O.[Cl-].[NH4+].O.[CH3:22][C:23]([CH3:25])=O>[Zn]>[CH3:22][C:23](=[N:1][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:4]1)[CH3:25]
Reactant: O=NN1CC(c2ccncc2)Cc2ccccc21
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccncc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-nitroso-3-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline (0.41 g, 0.00171 mol) in acetone (22 mL) was added saturated ammonium chloride solution (1.4 mL) and water (1.4 mL) at RT. The resulting brown colored reaction mixture was cooled to 0° C., and then zinc dust (0.669 g, 0.0102 mol) was added portionwise at 0° C. After addition, the reaction mixture was warmed to RT and stirred for 1 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure and the residue extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.3 g).