Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH2:9])[CH3:8].[CH3:26][CH:27]1[CH2:33][C:32](=[O:34])[O:31][C:29](=[O:30])[CH2:28]1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH:9][C:32]([CH2:33][CH:27]([CH3:26])[CH2:28][C:29]([OH:31])=[O:30])=[O:34])[CH3:8]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CC(N)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CC(=O)O)CC(=O)NC(C)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
20 mg of (1RS,2RS,3E)-2-(3,4-dichlorobenzyl)-1-methyl-4-(2-naphthyl)-3-butenylamine was dissolved in 1 ml of methylene chloride, and 10 mg of 3-methylglutaric anhydride and 4 μl of triethylamine were added thereto. The mixture was stirred at room temperature for 3 hours. A saturated sodium carbonate aqueous solution and methylene chloride were added to the reaction solution, and the mixture was stirred for 30 minutes. Then, the organic layer was collected by separation, washed with 1N hydrochloric acid and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-200, 2 g; chloroform/methanol=20/1) to obtain 16 mg (yield: 74%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4-chloro-2-methyl-5-nitrophenol (18.8 g, 100 mmol) in DMF (200 ml) was added potassium carbonate (13.8 g, 100 mmol) and methyl iodide (21.3 g, 150 mmol). The mixture was stirred for about two hours at room temperature. 5% Citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated under reduced pressure which gave the title compound (20 G, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][N:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:42][S:41][C:38]1[CH:37]=[N:36][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[N:40][CH:39]=1
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Reactant: CSc1cnc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(SC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 51 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (89 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methylsulfanyl-pyrimidine (71 mg) were added and the mixture was heated to 75° C. for 48 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give ethanesulfonic acid [6-[2-(5-methylsulfanyl-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (58 mg) as a white powder. LC-MS: tR: 4.15, [M+H]+: 572.19.
Reaction SMILES: C([O:5][C:6](=[O:9])CI)(C)(C)C.CCOCC.C([O:19][C:20]([CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:33][CH:34](OCC)[CH2:35][C:36](=C=O)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:32])[C:24]1=[O:48])=[O:21])(C)(C)C>CCCCCC>[C:20]([CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:33][CH:34]([C:6]([OH:9])=[O:5])[CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:32])[C:24]1=[O:48])([OH:19])=[O:21]
Reactant: CCOC(CC(=C=O)c1ccccc1)NC1(C)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Reactant: CC(C)(C)OC(=O)CI
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(NC(CCc2ccccc2)C(=O)O)C(=O)N(CC(=O)O)c2ccccc21

Procedure:
This above lactam was alkylated with t-butyliodoacetate as described in Example 1, Step B, to afford, after chromatography (silica, 2 ether: 1 hexane), 1-t-butyoxycarbonylmethyl 3-(1-ethoxy-carbonyl-3-phenylpropyl)amino-3-methyl-1,2-dihydro-2-oxo-3H-indole. NMR (CDCl3): δ1.1 (t, 3H); 1.5 (s, 9H); 1.55 (s, 3H); 1.8-3.2 (m, 6H); 3.9 (s, 2H); 4.4 (s, 2H); 7.1 (br.s., 9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[Cl:25]N1C(=O)CCC1=O>C(#N)C>[Cl:25][C:12]1[C:13](=[O:16])[O:14][CH2:15][C:11]=1[N:10]([CH2:9][C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(Cc1cnc(Cl)c(Cl)c1)C1=C(Cl)C(=O)OC1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
162 mg (0.59 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10) are dissolved in 20 ml of acetonitrile, and 90 μl (0.65 mmol) of triethylamine and 158 mg (1.19 mmol) of N-chlorosuccinimide are added at room temperature. After 1 hour of stirring, the mixture is concentrated under reduced pressure. Purification of the residue by column chromato-graphy on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 153 mg (67% of theory) of 3-chloro-4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.
Reaction SMILES: O=S(Cl)[Cl:3].[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][N:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:3])[CH:9]=[CH:8][N:7]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccnc(Cl)c1
Yield: 97.5 %

Procedure:
SOCl2 (4.2 g, 35.5 mol) was added dropwise to a suspension of the alcohol (5 g, 34.8 mmol) in CH2Cl2 (50 mL) at −5° C. with stirring. The mixture was stirred at room temperature overnight, then quenched with water (100 mL), and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/5) and afforded the title compound (5.5 g, near quantitative yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[O:26][C:22]([CH3:21])=[CH:23][CH:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)o1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-methyl-2-furancarboxylic acid (CAN 1917-15-3) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 409.574 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([O:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1

Procedure:
A stirred mixture of 4-bromo-2,6-difluorophenol (36 g, 0.172 mole), benzylchloride (21.77 g, 0.172 mole), and potassium carbonate (25 g, 0.18 mole) in demethylformamide (300 ml) was heated at 80°-90° for four hours. After cooling, the solvent was evaporated and ether added to the residue. The insoluble inorganic salts were removed by filtration, and solvent evaporated from the filtrate. The oily residue was subjected to bulb-to-bulb vacuum distillation on Kugelrohr apparatus to give the desired product as a nearly colorless oil (41 g, 80 percent): R.I.=1.5602 @25° C.; NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:22]O>>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCC/C=C\CCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC/C=C\CCc1ccccc1

Procedure:
A solution of (Z)-8-phenyl-5-octenoic acid (12.6 g), see Example 1(a), and concentrated sulphuric acid (0.1 ml) in methanol (300 ml) was heated under reflux for 2 hours. The solution was evaporated and the residue distilled under vacuum to give the ester b.p. 110° to 113° C./0.1 mm.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:6]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cccc(CC2CC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cccc(CC2CC2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(cyclopropylmethyl)phenyl]methanol (1.67 g, 10.3 mmol) in carbon tetrachloride (100 mL) was added polystyrene bound triphenyl phosphine (2.15 mmol/g, 9.57 g, 20.6 mmol). After stirring at 100° C. overnight the resin was filtered of and the solvent was removed under vacuum to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[N:28]=[CH:27][CH:26]=[N:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15]C(=O)OC(C)(C)C)=[O:8].Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[NH2:15][C@H:11]1[CH2:12][CH2:13][CH2:14][C@@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:23]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:24]1[N:25]=[CH:26][CH:27]=[N:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-[5-chloro-2-(2H-1,2,3-triazol-2-yl)benzamido]cyclopentyl]carbamate (170 mg, 0.418 mmol) in DCM (5 ml) was added HCl in 1,4-dioxane (4 M, 3 ml). The reaction was stirred at room temperature overnight and then concentrated in vacuo. The solid was triturated with diethyl ether (3×1 ml) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:31]=[CH:32][C:33]=2[F:34])[CH2:24][CH2:23]1>>[NH2:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:31]=[CH:32][C:33]=2[F:34])[CH2:24][CH2:23]1)=[O:5]
Reactant: NC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cc(NC(=O)C3CC3)ccc2F)CC1
Product: NC(C(=O)NCCCN1CCC(c2cc(NC(=O)C3CC3)ccc2F)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 174 was prepared from amino(diphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}cyclopropanecarboxamide according to the procedures described in Scheme 12; ESMS m/e: 529.4 (M+H)+.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Br:4][C:5]1[C:15]([O:16][CH3:17])=[C:14](Br)[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([S:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCS
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(SCC)c(OC)c1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl mercaptan (5 ml) was added to a suspension of ethyl 2,4-dibromo-3-methoxybenzoate (10.0 g) and potassium carbonate (9.0 g) in dimethylformamide (DMF). The mixture was stirred at room temperature for 48 hours, water was added and the mixture was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by medium pressure chromatography eluted with a mixture of ethyl acetate and cyclohexane to give ethyl 2-bromo-4-(ethylsulphenyl)-3-methoxybenzoate (3.98 g) as an oil NMR (CDCl3) 1.35(m,6H) 2.9(q,2H) 3.8(s,3H) 4.4(q,2H) 7.1-7.4(m,2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH:20]([CH3:23])[C:21]#[N:22].CO>CCCCCCC>[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH3:23])#[N:22]
Reactant: CC(N)C#N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Solvent: CO
Solvent: CCCCCCC
Product: CC(C#N)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-propanenitrile monohydrochloride (CAN 2134-48-7) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 286.1552 (M+H)+, αD20 (MeOH)=−9.6°.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]([N:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:31])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]2=[O:44])=[CH:7][C:8]([F:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)#[N:2].[O:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([CH2:3][O:4][C:5]1[C:6]([N:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([NH:50][C:47]4[CH:48]=[CH:49][O:45][N:46]=4)(=[O:31])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]2=[O:44])=[CH:7][C:8]([F:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)#[N:2]
Reactant: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of perfluorophenyl 1-(5-(cyanomethoxy)-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (250 mg, 0.394 mmol), isoxazol-3-amine (40.8 μl, 0.552 mmol) and THF (3940 μl) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF, 985 μl, 0.985 mmol) was added dropwise. The whole was warmed to rt and stirred for 30 min. An additional 1 mL of 1M LHMDS in THF was added and stirred for 30 min. The whole was quenched with 0.2 mL of TFA and concentrated. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and concentrated. Precipitate was filtered with an aid of water, dried to afford pink solid. m/z (ESI), [M+H]+=535.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 5.11-5.33 (m, 2 H) 6.45 (d, J=1.76 Hz, 1 H) 6.77-6.96 (m, 2 H) 7.28-7.46 (m, 1 H) 7.50-7.59 (m, 2H) 7.59-7.72 (m, 3 H) 7.87 (dd, J=8.98, 2.08 Hz, 1 H) 8.26 (d, J=9.83 Hz, 1H) 8.40 (d, J=2.03 Hz, 1 H) 8.73 (d, J=1.76 Hz, 1 H) 11.66 (br. s., 1 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1ccc(I)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
A 500 ml round-bottomed flask is charged with 66 g of 2-bromo-1-(4-iodophenyl)ethanone in 140 ml of DMF and 38 g of potassium phthalimide. The mixture is stirred at RT for 4 h and the precipitate formed is filtered off on a glass frit and washed with 3 times 50 ml of isopropyl ether. Drying under RP gives 80 g of 2-[2-(4-iodophenyl)-2-oxoethyl]isoindole-1,3-dione in the form of a white solid, which is used as it is in the following step. MS (E/I): m/z=391 (M+); 1H NMR: 5.21 (s, 2H); 7.84 (d, J=8.5 Hz, 2H); from 7.88 to 7.98 (m, 4H); 8.00 (d, J=8.5 Hz, 2H). m.p. (Kofler): 230° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:43]=[C:42]([NH:44][C:45]([N:47]2[CH2:51][CH2:50][N:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:48]2=[S:58])=[O:46])[CH:41]=[CH:40][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)[S:20][C:13]=12>C(Cl)Cl>[F:8][C:9]1[CH:43]=[C:42]([NH:44][C:45]([N:47]2[CH2:51][CH2:50][N:49]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:48]2=[S:58])=[O:46])[CH:41]=[CH:40][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])=[CH:25][N:26]=3)[S:20][C:13]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=S)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=S)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
TFA (1 ml, 12.98 mmol) was added to a suspension of 302 (0.093 g, 0.128 mmol) in DCM (1.000 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, the residue was dissolved in DCM, washed with 1N NaOH solution, water, dried over anhydrous sodium sulfate and concentrated affording title compound 303 (0.0714 g, 0.109 mmol, 85% yield) as white solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][CH2:18][O:19][N:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23]=2[CH:22]=[CH:21]1.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH:35]([C:21]1[N:20]([O:19][CH2:18][O:17][CH3:16])[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23]=2[CH:22]=1)=[O:36]
Reactant: CN(C)C=O
Reactant: COCOn1ccc2c(C(=O)OC)cccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOn1c(C=O)cc2c(C(=O)OC)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (1.97 g) in tetrahydrofuran (24.0 ml) was added dropwise n-butyllithium (6.8 ml, 1.64M solution in n-hexane) at −40° C. and the mixture was stirred at 0° C. for 30 minutes. A solution of methyl 1-methoxymethoxyindole-4-carboxylate (1.64 g) in tetrahydrofuran (12.0 ml) was added to the above solution at −60° C. and the solution was stirred at the same temperature for 30 minutes. A solution of N,N-dimethylformamide (662 mg) in tetrahydrofuran (9.0 ml) was added to the reaction mixture at −60° C. and the solution was stirred at the same temperature for 2 hours. The temperature was raised to −30° C. and the reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous solution was extracted with ethyl acetate (80 ml) and the organic layer was washed with brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give methyl 2-formyl-1-methoxymethoxyindole-4-carboxylate (1.15 g).
Reaction SMILES: O=[C:2]=[N:3]S(Cl)(=O)=O.[C:8]12([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][N:10]1[CH:19]=[CH:20][CH:21]=[C:9]21.CN(C)C=O>C1COCC1>[C:2]([C:19]1[N:10]2[CH2:11][CH2:12][N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]3([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23][CH2:22]3)[C:9]2=[CH:21][CH:20]=1)#[N:3]
Reactant: CCOC(=O)N1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of N-(oxomethylene)sulfamoyl chloride (23.9 μL, 0.27 mmol) in THF (200.0 μL) was slowly added to a solution of 1-tert-butyl 2′-ethyl 3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate (100 mg, 0.27 mmol) in THF (1.0 mL) at −78° C. under nitrogen. The reaction mixture was stirred for 1 hour at −78° C. N,N-dimethylformamide (39.9 μL, 0.51 mmol) was then slowly added to the cold reaction mixture. The reaction mixture was then allowed to slowly warm to room temperature. The reaction was filtered and purified by reverse phase preparatory-LC-MS (10-99% CH3CN/H2O) using HCl modifier to give 1-tert-butyl 2′-ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate. ESI-MS m/z calc. 388.2, found 389.3 (M+1)+; Retention time: 1.82 minutes (3 minute run).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](C4NC=CN=4)=[O:24])[CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1.[NH:36]1[CH2:39][CH2:38][CH2:37]1>C1COCC1>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([N:36]4[CH2:39][CH2:38][CH2:37]4)=[O:24])[CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CN(CC2CCN(C(=O)c3ncc[nH]3)CC2)CCO1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: CCOc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CN(CC2CCN(C(=O)N3CCC3)CC2)CCO1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A solution of (S)-4-amino-5-chloro-2-ethoxy-N-[{4-[(1-imidazolecarbonyl-4-piperidinyl)-methyl]-2-morpholinyl}methyl]benzamide (Example 206) (1.07 g) and azetidine (0.25 g) in THF (15 ml) was heated to reflux for 19 hours with stirring. After cooling to room temperature, the reaction solution was dried under reduced pressure to be solidified, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (0.43 g) as a white solid. Melting point 166-168° C. (recrystallized from EA/H)