Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30].C(N)(=[S:40])C>CN(C=O)C.C(OCC)(=O)C>[SH:40][C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30]
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: CC(N)=S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(S)c2c1
Temperature: 80 °C
Yield: 71 %

Procedure:
Diazabicycloundecene (DBU) (1.8 mL, 12.3 mmol) is added to a room temperature solution of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (1.0 g, 4.1 mmol) and thioacetamide (1.0 g, 13.1 mmol) in 10 mL of DMF. The mixture is warmed to 80° C. for 5.5 hours. The reaction mixture is allowed to cool and is diluted with ethyl acetate and washed with 1N HCl and water. The organic layer is extracted four times with 1N NaOH followed by water. The basic layers are combined and acidified with 6N HCl. The precipitate is filtered and washed with water. Recrystallization from ethyl acetate:hexane gives 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide in 71% yield; mp=205° C. dec.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(F)c1OC

Procedure:
In the same way as in Example 29, 210 mg (0.64 mmol) of (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 132 mg (0.97 mmol) of 5-aminoquinolin-2(1H)-one and 0.27 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 234 mg of crude imine are cyclized in the same way as in Example 29 at −20° C. with 2 ml (2 mmol) of 1 M boron tribromide solution to give the desired product. Preparative thin-layer chromatography on silica gel (hexane/2-propanol 17%) yields 15.4 mg of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)[C:53](NC3C=CC(C(O)=O)=CC=3)=[O:54])C3C=C(F)C(F)=CC=3N=2)=CC=1.COC(=O)C1C=CC(N)=C(OC)C=1>N1C=CC=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([O:54][CH3:53])[CH:6]=1
Reactant: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: COC(=O)c1ccc(N)c(OC)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(OC)c1
Yield: 74 %

Procedure:
This compound was synthesized in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c), 4-amino-3-methoxy-benzoic acid methyl ester and using pyridine as a base to afford the title compound as a colorless solid (74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:48]=[CH:47][C:46]([CH3:49])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[N:44]=[CH:45][C:46]([CH3:49])=[CH:47][N:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cnc(-c2cc(C)c(Br)c(C)c2)nc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ncc(C)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-pyrimidine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.27 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15](OCC)=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3ccccc3)cc(CO)cn2c1C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A solution of 1.2 g of 8-benzyloxy-6-ethoxycarbonyl-2,3-dimethylimidazo[1,2-a]pyridine in 20 ml of tetrahydrofuran is treated in small portions with 0.2 g of lithium aluminum hydride at room temperature stirred for one hour and treated successively with 0.2 ml of water, 0.2 ml of 6 molar sodium hydroxy solution and 0.6 ml of water. It is then extracted twice with methylene chloride (50 ml each), the combined organic phases are concentrated to dryness in vacuo and the residue is purified on silica (eluent: methylene chloride/methanol 13/1). 0.4 g of the title compound of melting point 213-5° C. (acetone) is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: NC(CO)CO
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(NC(CO)CO)c2s1

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and 2-amino-1,3-propandiol.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([N+:13]([O-])=O)/[CH:10]=[N:11]\[OH:12].C(O)(=[O:18])C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[N:13]=[C:9]([OH:18])[CH:10]=[N+:11]1[O-:12]
Reactant: Nc1ccccc1Cl
Reactant: O=[N+]([O-])C/C=N\O
Reactant: CC(=O)O
Product: [O-][n+]1cc(O)nn1-c1ccccc1Cl
Reaction time: 10 h

Procedure:
100 g of oxime-hydrazone II (R = 2-chlorophenyl), prepared from diazotized 2-chloroaniline and methazonic acid, is stirred in 1000 ml of 90% acetic acid at room temperature. There are formed after a short time nitrous gases, and a dark clear solution is obtained. After 10 hours, the solution is concentrated by evaporation to dryness, and the residue is stirred into ether, filtered off under suction and dried.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]I>C1COCC1>[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: CC[C@H](C)CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1ccco1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of furan (8.16 g, 0.13 mol) in dry THF (100 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (28.0 mL, 2.5 M, 70.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of (S)-2-methylbutyliodide (10.0 g, 50.5 mmol) in dry THF (20 mL) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction was quenched by water (20 mL) and the mixture was poured into water (200 mL), and the resulting mixture was extracted with ether (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as eluent, leading to a colorless oil as the product. (6.18 g, 88.5%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][CH2:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: NCc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccccn4)cc3)oc2C)cc1
Yield: 79.8 %

Procedure:
Reaction of oxalyl chloride (75 λL, 0.9 mmol) and benzoic acid 4 (215 mg, 0.6 mmol) with subsequent coupling to 2-pyridinylmethylamine (68 λL, 0.6 mmol) gave benzamide 8 (221 mg, 83%) as a white powder: mp (EtOAc) 154-155° C.; 1H NMR δ 9.21 (t, J=6.0 Hz, 1H, CONH), 8.52 (dd, J=4.8, 1.5 Hz, 1H, H-6′), 8.04 (d, J=8.6 Hz, 2H, H-2, H-6), 7.91 (d, J=8.6 Hz, 2H, H-3, H-5), 7.77 (dt, J=7.8, 1.8 Hz, 1H, H-4′), 7.67 (d, J=8.3 Hz, 2H, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 7.35 (d, J=7.8 Hz, 1H, H-3′), 7.27 (dd, J=7.7, 4.8 Hz, 1H, H-5′), 4.63 (s, 2H, CH2SO2), 4.59 (d, J=6.0 Hz, 2H, CH2N), 2.41 (s, 3H, CH3), 2.14 (s, 3H, CH3); 13C NMR δ 165.6, 158.6, 158.0, 149.9, 148.8, 144.5, 136.7, 135.6, 135.5, 129.6 (2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 122.1, 121.0, 53.0, 44.8, 21.0, 9.7; MS m/z 462.6 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.03; H, 5.00; N, 9.11%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Mg].[CH3:15][C:16]1[O:20][C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:18][C:17]=1[CH:25]=[O:26].[C:27](OC(=O)C)(=[O:29])[CH3:28]>O1CCCC1>[CH3:15][C:16]1[O:20][C:19]([Si:21]([CH3:22])([CH3:24])[CH3:23])=[CH:18][C:17]=1[CH:25]([O:26][C:27](=[O:29])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCBr
Reactant: Cc1oc([Si](C)(C)C)cc1C=O
Reactant: CC(=O)OC(C)=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(C)=O)c1cc([Si](C)(C)C)oc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromododecane (261 mg, 0.11 mmol) and magnesium turnings (27 mg , 0.11 mmol) in tetrahydrofuran (7 ml) was refluxed under argon for 1 hour. After cooling to room temperature, a solution of 5-methyl-2-trimethylsilyl-4-furaldehyde (158.6 mg, 0.87 mmol ) in tetrahydrofuran (1 ml ) was added, followed by acetic anhydride (0.25 ml, 2.6 mmol) after 1 hour. Stirring was continued at room temperature overnight and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 1000 micron silica plate; developed with 5% ethyl ether/hexane). The title ester was obtained as a light yellow oil.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:8]=[CH:9][C:10]=1[F:11].[C:36]([O-:39])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[F:11][C:10]1[C:5]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:36]=[O:39])[CH:10]=2)=[CH:6][C:7]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(-c4cccc(C=O)c4)c3)c2)CC1
Yield: 161.5 %

Procedure:
To a solution of 3-formylphenyl)boronic acid (21 mg, 0.14 mmol) in dioxane (3 mL) and water (1 mL) was added 1,1-dimethylethyl 4-{[3-({[(3-bromo-4-fluorophenyl)methyl]amino}carbonyl)phenyl]methyl)-1-piperidinecarboxylate (70 mg, 0.14 mmol), K2CO3 (97 mg, 0.7 mmol) and Pd(PPh3)4 (8 mg, 0.007 mmol). The resulting solution was irradiated in a microwave reactor at 150° C. for 20 minutes then diluted with EtOAc (5 mL). The organic layer was separated and the aqueous layer was further extracted by EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by Gilson HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 90/10, v/v, over 12 min), to give the title compound (60 mg, 81%). LC/MS: m/z, 531 (M+H), 2.83 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@:10]1([OH:29])[C:22]2[CH:21]=[C:20]3[N:16]([CH2:17][CH2:18][C:19]43OCC[O:23]4)[C:15](=[O:27])[C:14]=2[CH2:13][O:12][C:11]1=[O:28])[CH3:9]>C(OCC)(=O)C>[CH2:8]([C@:10]1([OH:29])[C:22]2[CH:21]=[C:20]3[N:16]([CH2:17][CH2:18][C:19]3=[O:23])[C:15](=[O:27])[C:14]=2[CH2:13][O:12][C:11]1=[O:28])[CH3:9]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC12OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To 90 ml of 90% trifluoroacetic acid, 3.5 g of (4S)-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,10(4H)-dione were added at room temperature over 5 minutes, followed by Stirring at the same temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, followed by the thorough removal of the solvent by a vacuum pump. To the residue so obtained was added 20 ml of ethyl acetate. The crystals precipitated were collected by filtration, whereby 2.4 g of the title compound were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([NH2:23])=O)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](=[S:33])[NH2:23])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=O)cc3c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=S)cc3c2)cn1
Yield: 78.4 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (4.5 g) in tetrahydrofuran (100 mL) was added a Lawesson's reagent (6 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (3.7 g, yield 78%) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[N+](=[CH2:24])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][CH3:24])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 71.6 %

Procedure:
In 6 ml of tetrahydrofuran was dissolved 200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, and a solution of about 40 mg of diazomethane in diethyl ether was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, acetic acid was added until foaming was not caused in the reaction mixture, after which the solvent was removed by distillation under reduced pressure. The crystals thus obtained were washed with 6 ml of isopropyl alcohol to obtain 150 mg (yield 71.6%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate having a melting point of 160°-161° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:22]I.[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[CH2:27]CBr>CN(C)C=O.O>[CH3:22][O:15][C:13](=[O:14])[CH2:12][CH:10]1[CH2:9][N:8]([CH2:6][CH2:27][C:26]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:25]=2[F:24])[CH2:11]1
Reactant: CI
Reactant: Fc1ccc(CCBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1CN(CCc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A mixture of [1-(tert-butoxycarbonyl)azetidin-3-yl]acetic acid (2 g, 9.24 mmol), potassium carbonate (1.54 g, 11.1 mmol) and methyl iodide (2.89 mL, 46.5 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with dichloromethane (x2). The combined organic layers were washed with saturated sodium hydrogencarbonate solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) added. The reaction was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was dissolved in N,N-dimethylformamide (30 mL). 2,4-Difluorophenethyl bromide (2.26 g, 10.2 mmol) and potassium carbonate (5.14 g, 37.2 mmol) were added and the reaction heated at 60° C. overnight. The cooled reaction mixture was diluted with water and extracted with dichloromethane (x3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% methanol/dichloromethane, to give methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetate (1.3 g, 52%). 1H NMR (360 MHz, CDCl3) δ 7.15–7.09 (1H, m), 6.79–6.71 (2H, m), 3.64 (3H, s), 3.48–3.44 (2H, m), 2.87–2.75 (3H, m), 2.60 (4H, s), 2.57 (2H, d, J=7.1 Hz); m/z (ES+) 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](Cl)=[O:6].ClC1C=C(C(F)(F)F)C=C(Cl)C=1F.S(=O)(=O)(O)[OH:27].ClS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([OH:27])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: O=C(Cl)c1cc(Cl)c(F)c(Cl)c1
Agent: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)Cl
Product: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Temperature: 80 °C
Yield: 49 %

Procedure:
3,5-dichloro-4-fluorobenzoyl chloride can be prepared as follows: To a round bottom flask with nitrogen purge through a 10% aqueous NaOH trap, was added 3,5-dichloro-4-flurobenzotriflouride (5.00 g, 21.46 mmol, Aldrich), concentrated sulfuric acid (4.30 g, 42.92 mmol), and finally chlorosulfonic acid (5.15 g, 43.78 mmol). The reaction began to bubble immediately. After the bubbling subsided, the mixture was heated to 80° C. for 1 hr, cooled to room temperature, and added cautiously to stirred ice water. This was extracted twice with methylene chloride. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to give a white solid (2.19 g) of 3,5-dichloro-4-fluorobenzoic acid in 49% yield. 1H-NMR (CD3COCD3, 300 MHz) δ (ppm): 7.95 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].C([Mg:18][Br:19])C.[CH2:20]1[O:22][CH2:21]1>C1COCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][CH2:20][CH2:21][O:22][Mg:18][Br:19])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CC[Mg]Br
Reactant: C1CO1
Reactant: C#Cc1ccc(-c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(C#CCCO[Mg]Br)cc2)cc1

Procedure:
19.6 g. of 4-ethynyl-4'-fluorobiphenyl in 200 ml. THF is converted with an excess of ethyl magnesium bromide to the Grignard compound, to which is added 100 ml. of THF and then a solution of 5 g. of ethylene oxide in 10 ml. of THF. After subsidance of the exothermic reaction, the mixture is heated under reflux for 1 hour. 4-(4'-Fluoro-4-biphenylyl)-3-butyn-1-oxymagnesium bromide is thereby formed in situ. To this is added 150 ml. of 1 N hydrochloric acid. After stirring for 20 minutes at 20° and the usual work up, 4-(4'-fluoro-4-biphenylyl)-3-butyn-1-ol, m.p. 134°, is obtained.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]#[N:10].Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH:5]3[CH2:6][CH2:2][N:3]([CH2:8][C:9]#[N:10])[C:4]3=[O:7])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:19]=1
Reactant: N#CCN1C(=O)CCC1Br
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC#N)C3=O)CC2)cc1
Yield: 77.3 %

Procedure:
To a solution of 2-(2-bromo-5-oxopyrrolidin-1-yl)acetonitrile (730 mg, 3.6 mmol) and (4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (920 mg, 3.6 mmol) in acetonitrile (4 mL) was added triethylamine (1.5 mL, 11 mmol). The mixture was microwave at 130° C. for 12 minutes. The solvent was removed in vacuo and the residue was taken up in methylene chloride and water. The organic layer was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide slightly yellow oil (950 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 4.22-4.39 (m, 2H), 3.90 (s, 3H), 3.57 (dt, J=22.6, 9.0 Hz, 2H), 3.40-3.51 (m, J=8.5 Hz, 1H), 3.23-3.39 (br s, 1H), 2.93-3.20 (m, 3H), 2.33-2.61 (m, 2H), 2.13-2.31 (m, 1H), 1.83-2.03 (m, 4H). HRMS calculated for C13H23N3O3 342.1818. found (ESI, [M+H]+), 342.1830.