Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:7]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: COCCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-Cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.46 g, 4.18 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.31 g, 5.01 mmol) were dissolved in dichloromethane (10 mL) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-(2-methoxy-ethoxymethyl)-8H-pyrido[2,3-d]pyrimidin-7-one as a white waxy solid (0.60 g, 39.3%). 1H NMR δ (400 MHz, CDCl3) 8.94 (s, 1H), 7.88 (t, J=1.7 Hz, 1H), 5.95 (m, 1H), 4.52 (d, J=1.7 Hz, 1H), 3.80 (m, 2H), 3.65 (m, 2H), 3.43 (s, 3H), 2.98 (s, 3H), 2.25 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][S:28][C:29]1[CH:30]=[C:31]([C:35]([C:37]2[N:38]=[CH:39][N:40]3[CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[S:42][C:41]=23)=[O:36])[CH:32]=[N:33][CH:34]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:43]3[S:42][C:41]4=[C:37]([C:35]([C:31]5[CH:32]=[N:33][CH:34]=[C:29]([S:28][CH3:27])[CH:30]=5)=[O:36])[N:38]=[CH:39][N:40]4[CH:44]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(SC)c3)c2s1
Product: CSc1cncc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)c1
Yield: 50.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (100 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 169 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 179 mg of 7-(5-methylthiopyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:18][OH:19])[CH2:7]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@H:8]([CH2:18][O:19][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1COS(C)(=O)=O
Reaction time: 9 h
Yield: 101.5 %

Procedure:
To a solution of (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (1.38 g, 3.82 mmol) in methylene chloride (30 mL) was added triethylamine (0.78 mL, 5.72 mmol) followed by methanesulfonyl chloride (0.36 mL, 4.58 mmol) and the mixture was stirred at 20° for 9 hrs. Most CH2Cl2 was then removed by evaporation in vacuo, and the residue was diluted with ethyl acetate and washed with aqueous NaHCO3 followed by water. Drying with Na2SO4 followed by evaporation in vacuo gave 1.70 g of crude (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(methanesulfonyloxymethyl)pyrrolidine, which was used without further purification.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[C:21](Cl)(Cl)(Cl)[Cl:22].CCCCCC>C(O)(=O)C>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:21][Cl:22])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2ccccc21
Reactant: ClC(Cl)(Cl)Cl
Agent: C=O
Agent: Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C(c1ccccc1)N1CCc2cc(CCl)ccc21
Yield: 60 %

Procedure:
1-Benzoyl-2,3-dihydro-1H-indole (Beilstein, 20, 275) (5.58 g, 25 mmole) is dissolved in 50 ml of glacial acetic acid, then 56 ml (ca 70 mmoles) of 40% formaldehyde are added, and dry hydrogen chloride passed into the solution which is maintained at 70° for 3 hours. The solution is evaporated, and the residue dissolved in benzene, and again evaporated to dryness to give 6.53 g of crude product. This residue is treated with carbon tetrachloride-hexane to give 4.05 g (60%) of 1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole, m.p. 107.5°-110.0°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH:17]([C:36]([N:39]3[CH2:44][CH2:43][S:42][CH2:41][CH2:40]3)=[O:37])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)[C:19](=[O:21])[CH2:20]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Reactant: C1CSCCN1
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)N1CCSCC1
Product: Cl

Procedure:
Similarly to Example 116 and using 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylic acid (0.15 g) obtained in Example 110 and thiomorpholine (0.041 ml), the title compound (0.07 g) was obtained as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]5[CH:35]=[N:36][CH:37]=[CH:38][C:27]4=5)[N:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:47]1[C:48]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]=[CH:45][C:46]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]5[CH:35]=[N:36][CH:37]=[CH:38][C:27]4=5)[N:21]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cc(-c3ccc(-c4ccc5ccccc5c4)cc3)cc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)n2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
To 4.6 g of the 4′-(4-bromophenyl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine obtained in Example 4 were added 1.4 g of 2-naphthaleneboronic acid, 0.5 g of tetrakis(triphenylphosphine)palladium, 21 mL of a 2 M aqueous potassium carbonate solution, 72 mL of toluene, and 18 mL of ethanol, followed by heating with reflux while stirring for 6 hours. After cooling to room temperature, a precipitate was collected by filtration. To the precipitate, 200 mL of o-dichlorobenzene was added and insoluble matter was removed by filtration. The filtrate was concentrated under a reduced pressure to obtain a concentrate. The concentrate was dissolved in chloroform and subjected to adsorptive purification with NH silica gel. Thereafter, the filtrate was concentrated under a reduced pressure to obtain a crude product. The crude product was washed with ethyl acetate to obtain 3.5 g (yield, 69%) of 4′-(4-naphthalen-2-yl-phenyl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine (Compound 134) as a white powder.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[Br:22][C:18]1[N:17]=[C:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[NH:8]2)=[O:23])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(Br)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(Br)n1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-3-(6-bromo-pyridin-2-ylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (561 mg, 1.47 mmol) in CH2Cl2 (11 mL) was added TFA (1.13 mL, 14.7 mmol) and the solution was stirred at RT overnight. CH2Cl2 was concentrated and the crude residue was dried under high vacuum to give the desired material which was used without further purification in the next step. MS: 282.1/284.1 [M+H]+, 304.0/306.1 [M+Na]+, 563.1/565.2 [2M+H]+; tR (HPLC conditions f): 0.96 min.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A mixture of 123 (700 mg, 1.77 mmol) and 2-methoxyethanamine (185 □L, 160 mg, 2.12 mmol) in DCM (7 mL) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (526 mg, 2.48 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (20 mL). The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 4-8% MeOH/DCM to afford 124 (675 mg, 65% yield). MS (m/z): 455.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2cccc(C)c2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(C)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 2-amino-4-(3-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 2 & 3, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 63% yield.
Reaction SMILES: Cl.[F:2][CH:3]([F:14])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[OH:13].C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[NH:28][C:27](=O)/[C:26]/2=[CH:35]/OC>CN(C)C=O>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[N:28][CH2:27]/[C:26]/2=[CH:35]\[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:3]([F:14])[F:2])=[C:6]([OH:13])[CH:7]=1
Reactant: NCc1ccc(OC(F)F)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cc(CN/C=C2\CN=Cc3ccc(Br)cc32)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
An amount of 90 mg (0.40 mmol) of 4-difluoromethoxy-3-hydroxy benzylamine hydrochloride, is dissolved in N,N-dimethylformamide (4 mL). 50 ul (0.75 mmol) of triethylamine is added followed by 112 mg (0.40 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, the solvent is removed in-vacuo and the residue dissolved in 7.5% methanol in chloroform and passed thru a short pad of Florisil eluting with 7.5% methanol in chloroform, the eluate is evaporated and the solid triturated with ether, filtered and washed several times with anhydrous ether to give 116 mg of a pink solid (67% yield); mp 256-8° C., MS data ES(−) 437.0, 439.0 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=O)[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1.Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=[N:18][OH:19])[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1
Reactant: NO
Reactant: COc1ccc2c(c1)CC1CCC(C2)C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC1CCC(C2)C1=NO
Yield: 86.9 %

Procedure:
2-Methoxy-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (20.0 g; 0.1 mole) is reacted with hydroxylamine hydrochloride (20.0 g; 0.29 mole) in ethanol (100 ml) and pyridine (100 ml) to yield 20.1 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[CH:18]=[C:19]([S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[S:23](=[O:26])(=[O:25])[NH2:24]>CC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([S:27]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][CH3:8])[CH2:11][CH2:12]2)(=[O:28])=[O:29])[CH:20]=[CH:21][C:22]=1[S:23]([NH2:24])(=[O:25])=[O:26]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: COC1CCNCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC1CCN(S(=O)(=O)c2ccc(S(N)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Triethylamine (4.2 ml) and 4-methoxypiperidine (3.15 g) were added to a solution of 3-chloro-4-sulphamoyl-benzene sulphonyl chloride (8.7 g) in acetone (100 ml). The mixture was stirred at room temperature for 1 hour and then poured into 50 ml of N-hydrochloric acid. The resulting product was removed by filtration, washed with water and recrystallized from isopropanol to give the desired compound (8.4 g), m.p. 165°-167°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4](/[CH:8]=[N:9]/[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:22]/[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])/[C:20]#[N:21])=[C:15]([F:28])[CH:14]=1.[OH-].[K+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]2[C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=3[F:28])([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]2[NH:9][CH2:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=3[F:28])([C:20]#[N:21])[CH:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: C/N=C/c1cccc(Cl)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CC1C(c2cccc(Cl)c2F)NCC1(C#N)c1ccc(Cl)cc1F
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %
Yield: 20.3 %

Procedure:
To a solution of [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (1.72 g, 10.00 mmol) and (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 10.00 mmol) in DMSO (10 mL) was added KOH powder (1.12 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with EtOAc three times (3×50 mL). The combined organic layers were washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash column (SiO2, 1%-15% of EtOAc in hexanes) after concentration to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (0.86 g, 20.3%; HRMS (ES+) m/z Calcd for C22H22Cl2F2N2+H [(M+H)+]: 423.1201, found: 423.1199) and rac (3S,4S,5S)-5-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)pyrrolidine-3-carbonitrile (0.66 g, 15.6%); HRMS (ES+) m/z Calcd for C22H22Cl2F2N2+H [(M+H)+]: 423.1201. found: 423.1202.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=O)(=[O:28])=[O:27].Cl.Cl.[N:40]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1.CCN(C(C)C)C(C)C>ClCCl.CO>[OH:46][CH:43]1[CH2:42][CH2:41][N:40]([CH:47]2[CH2:52][CH2:51][N:50]([C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([S:26]([CH3:25])(=[O:27])=[O:28])[CH:30]=3)=[O:34])[CH2:49][CH2:48]2)[CH2:45][CH2:44]1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: OC1CCN(C2CCNCC2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(C(=O)N2CCC(N3CCC(O)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
PyBrOP™ (25.3 g) was added to a stirred solution of 3-methanesulphonyl benzoic acid (10 g), [1,4′]bipiperidinyl-4-ol dihydrochloride (13 g, see Method D) and Hunig's base (34 ml) in dichloromethane (500 ml). The resulting mixture was stirred at RT overnight, then washed with saturated NaHCO3 solution (300 ml) followed by saturated brine (300 ml). The organic layer was dried (MgSO4) and evaporated to leave an oily residue. Column chromatography (silica, 20% methanol in DCM) gave the product as a white solid (16 g; MS: APCI+(M+H) 367).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:39]([C:38]1[CH:37]=[C:36]([C:34]#[C:35][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][C:14]=3[O:32][CH3:33])[N:3]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:40])[NH2:41]
Reactant: C#Cc1cccc(C(N)=O)c1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2cccc(C(N)=O)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I34) (0.098 g, 0.20 mmol), 3-ethynylbenzamide (I31) (0.038 g, 0.26 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol), triphenylphosphine (0.010 g, 0.04 mmol) and copper(I) iodide (0.009 g, 0.05 mmol) in DMF (2 mL), that had been degassed with nitrogen for 10 minutes, was added triethylamine (0.090 mL, 0.65 mmol). The mixture was degassed with nitrogen then heated to 120° C. for 25 minutes under microwave irradiation. On cooling to room temperature the resulting mixture was left overnight, then an additional portion of 3-ethynylbenzamide (I26) (0.047 g, 0.32 mmol) was added. After degassing with nitrogen the reaction was heated at 120° C. for 25 minutes under microwave irradiation. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (20-70% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 61%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.04 (dd, J=1.4, 1.4 Hz, 1H), 8.02 (s, 1H), 7.93 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 7.80 (m, 1H), 7.53 (m, 1H), 6.88 (dd, J=8.3, 1.6 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.27 (m, 2H), 3.91 (s, 3H), 2.81 (m, J=12.2 Hz, 2H), 2.64 (tt, J=12.2, 3.4 Hz, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.59 min; m/z 496.1 [(M-Boc)+H]+, 540.0 [(M-t-Bu)+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][C:6](=[CH2:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1.Cl.[CH3:31][O:32][NH2:33].CO.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:31][O:32][N:33]=[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:22][C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])=[CH:20][C:19]=2[Cl:29])=[CH2:18])=[CH:14][CH:13]=1)[CH3:16]
Reactant: CON
Reactant: C=C(COc1ccc(C(C)=O)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(COc1ccc(C(C)=NOC)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
286 mg of 1-(4-{2-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxymethyl]-allyloxy}-phenyl)-ethanone and 56 mg of O-methyl-hydroxylamine hydrochloride are introduced into 4 ml of methanol. 55 mg of sodium acetate are then added and the mixture is stirred for 24 hours at 25° C. The reaction mixture is diluted with 12 ml of ethyl acetate and washed twice with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Yield: 57.5 %

Procedure:
As described for example 91a, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (880 mg, 4.2 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, to the title compound (832 mg, 98%) which was obtained as an off white solid. MS: m/e=343.1 [M−H]−.