Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)[C:21]=1[C:22](O)=[O:23].CCN(C(C)C)C(C)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)[C:21]=1[C:22]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:23]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1c(F)cccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 1.09 g, 3.87 mmol) in DCM (13 ml) was added 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1186050-58-7; 0.802 g, 3.87 mmol), DIPEA (2.027 ml, 11.61 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.579 g, 4.26 mmol) and EDC (0.816 g, 4.26 mmol). The reaction was stirred at room temperature for 17 hours and was then partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic fit and concentrated in vacuo. The residue was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) and recrystallised from IPA to afford the title compound.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[C:7]([O:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:12]=[CH:11]2.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:5][C:6]1[C:7]2[O:22][CH2:23][CH2:24][C:25](=[O:27])[C:8]=2[CH:9]=[C:10]2[C:14]=1[N:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:12]=[CH:11]2
Reactant: O=C(O)CCOc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
SOCl2 (4.25 mL, 58.3 mmol) was added dropwise to a slurry of 3-((7-bromo-1-(4-fluorophenyl)-1H-indazol-6-yl)oxy)propanoic acid (98, R1=4-Fluorophenyl) (17.0 g, 44.8 mmol) and DCM (500 mL) under a nitrogen atmosphere at about 0° C. After about 10 min, the ice bath was removed. After about 1 h, SOCl2 (1.00 mL, 13.7 mmol) was added dropwise. After about 3 h, the solution was cooled to 0° C. and then aluminum chloride (18.0 g, 135 mmol) was added in three portions over about 15 min. The ice bath was allowed to thaw to rt over about 2 h. After about 1 h at rt, the mixture was poured into ice water (500 mL). After stirring for about 15 min, the layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organics were washed with water (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was slurried in EtOH (50 mL). The solid was collected by filtration rinsing with EtOH (2×10 mL) then dried under reduced pressure to afford 9-bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5(1H)-one (99, R1=4-Fluorophenyl) (13.3 g, 82% yield) as an ivory solid. LC/MS, method 3, Rt=2.26 min, MS m/z 361 and 363 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.42 (s, 1H), 7.61-7.54 (m, 2H), 7.42-7.33 (m, 2H), 4.66 (t, J=6.3 Hz, 2H), 2.89 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:31])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C(OCC)=O)=[C:19]([O:29][CH3:30])[CH:18]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([NH:11][C:12](=[O:31])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:29][CH3:30])[CH:18]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CCOC(=O)Oc1ccc(C=CC=CC(=O)NC/C=C(\C)CCC=C(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC=CC(=O)NC/C=C(\C)CCC=C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 1.61 g of 5-(4'-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoic acid geranylamide in 25 ml of methanol is added 10 ml of 2N aqueous solution of sodium hydroxide. The mixture is stirred at room temperature for one hour. The reaction mixture, after acidified with 1N hydrochloric acid, is extracted with chloroform. The organic layer is washed with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with methylene chloride is obtained 1.20 g of 5-(4'-hydroxy-3-methoxyphenyl)pentadienoic acid geranylamide (12). Spectroscopic data of the product support the structure of the formula (12) below.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3(O)[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1.C(N(S(F)(F)[F:30])CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:30])[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)COC1)n2C
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of (S)-3-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)oxetan-3-ol (127.6 mg, 0.364 mmol) in anhydrous DCM (8.0 mL) at −78° C. under N2 was added diethylaminosulfur trifluoride (59.5 μL, 0.436 mmol, 1.2 eq.). The reaction mixture was warmed to 0° C. over 3 h, stirred at RT for 2 h, and quenched with 1N sodium hydroxide solution. The reaction mixture was diluted with ethyl acetate. The two phases were separated, and the organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in hexane) to give the product as a foam (79.6 mg, 62.0%). 1H NMR (CDCl3, 500 MHz) δ ppm 6.10 to 4.40 (broad s, 2H), 5.30 to 5.19 (m, 2H), 5.10 (dd, J=20.7, 7.8 Hz, 2H), 4.04 to 3.98 (m, 1H), 3.83 to 3.73 (m, 2H), 3.68 (d, J=1.5 Hz, 3H), 3.61 (td, J=11.6, 2.8 Hz, 1H), 3.48 (broad s, 1H), 1.40 (d, J=6.8 Hz, 3H); LC-MS m/z (method A)=342 [M+H]+, RT=2.36 min.
Reaction SMILES: CC1(C)O[CH2:8][CH2:7][C@H:6]2N1[C:4](=[O:12])[C@@H:5]2[N+]#[C-].N(C(C)(C)C#N)=N[C:16](C)([CH3:19])[C:17]#N>C1C=CC=CC=1>[CH3:17][CH2:16][CH2:19][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:12]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: c1ccccc1
Product: CCCCCCCC=O
Yield: 896.5 %

Procedure:
A mixture of (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (150 mg), tribulyltinhydride (0.263 ml), and azobisisobutyronitrile (14 mg) in benzene (4.5 ml) was refluxed for 15 minutes. The resulting solution was chromatographed on silica gel (4.5 g) eluting with a mixture of benzene and acetone (15:1-6:1) to give the crude product (140 mg) as an oil, which was purified by silica gel (5 g) chromatography (eluate: a mixture of methylene chloride and ethyl acetate 30:1-5:1) to give (6R)-2,2-dimethyl-1-aza-3-oxabicycle[4.2.0]octan-8-one (98 mg) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[Cl:21][C:22]1[S:26][C:25]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)=[CH:24][CH:23]=1
Reactant: OCc1ccc(Cl)s1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl) methanol (166 mg) and tributylphosphine (388 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (422 mg), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (16.1 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3F)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-(1-[5-(2-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.89 (s, br, 1H), 7.72–6.88 (m, 11H), 5.59–5.48 (m, 1H), 3.70–3.48 (br, 2H), 3.05–2.84 (br, 2H), 2.82–2.58 (m, br, 4H), 2.58–2.40 (m, br, 2H), 2.22–1.82 (m, br, 6H), 1.71–1.42 (m, br, 2H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 589.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][O:18][CH3:19])=[C:11]([CH3:20])[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([O:16][CH2:17][O:18][CH3:19])=[C:13]([CH3:15])[CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1c(C)cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Yield: 90.7 %

Procedure:
Using 0.96 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate, 0.84 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.44 g of the desired compound were obtained.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21](CC(O)(C)C)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.I[CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (80 mg), 1-iodo-3,3,3-trifluoropropane (108 mg), and K2CO3 (63 mg) in N-methyl-2-pyrrolidone (2 mL) is stirred at room temperature for 4 h and then at 60° C. over night. Since conversion of starting material is still incomplete, K2CO3 (63 mg) and two portions of 1-iodo-3,3,3-trifluoropropane (54 mg each) are added while stirring the reaction mixture for two more days at 80° C. Water is added to the reaction mixture and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with brine dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→50:50). The crude product is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 3): tR=1.08 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1ccco1
Solvent: CO
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
Methyl N-cyano-2-furancarboximidate (0.32 g, 2.09 mmol) was dissolved in methanol (3 ml), 2-nitroxyethylamine nitrate (0.37 g, 2.19 mmol) and triethylamine (0.22 g, 2.19 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 25 g) eluting with dichloromethane. The eluted fractions were concentrated under reduced pressure and crystallized from dichloromethane to give the title compound (0.20 g, 0.89 mmol, yield: 45%) as colorless crystals.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.[CH3:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:24][CH:16]2[CH3:15])=[O:14])[N:4]=1
Reactant: CC1Cc2ccccc2N1
Reactant: COc1cc(Cl)nc(CC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(CC(=O)N2c3ccccc3CC2C)n1
Temperature: 20 °C

Procedure:
In a three-necked flask, under argon, 4 g of the sodium salt of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid (example 8b, step 3b) and 2.6 g of 2-methylindoline (6872-06-6, Aldrich) are placed in 3 ml of pyridine and 60 ml of DMF. The heterogeneous solution obtained is stirred at ambient temperature (20° C.), then N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added and stirring is maintained for 20 hours. The reaction mixture is concentrated in a rotary evaporator under vacuum, 100 ml of water are added, extraction is carried out with 3 times approximately 50 ml of dichloromethane, washing is carried out with 50 ml of saturated NaCl solution, drying is carried out over MgSO4 and filtration is carried out through a VF filter. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with dichloromethane. The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from diisopropyl ether, filtration is carried out, and drying is carried out at 20° C. 2-(4-Chloro-6-methoxypyrimidin-2-yl)-1-(2-methyl-2,3-dihydroindol-1-yl)ethanone is isolated (2.6 g) in the form of a solid (yield 46%) which is used as it is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:17].[OH-].[K+]>O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[NH:22]1[CH:21]=[CH:20][N:19]=[C:18]1[C:16]1[S:17][C:5]2[C:6]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:15]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)c1ncc[nH]1
Agent: [Fe+6]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3ncc[nH]3)nc12
Yield: 46.8 %

Procedure:
0.08 g of 1H-Imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.25 mmol) were taken up in water (2.0 ml) and treated with 0.056 g KOH (1.0 mmol) and 0.331 g of potassium hexacyano ferrate (1.0 mmol) at reflux for 1 h. After cooling to ambient temperature water (10 ml) was added and the mixture was filtered. The residue on the filter was dried in vacuo at 40° C. One obtained 0.037 g of 2-(1H-imidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (47%) as a yellow solid; M.p.: 228–230° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:7]1[C:8]2[CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][C:14]=2[C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])=[N:23][C:6]1=2
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 6 h
Yield: 19.6 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.20 g, 0.53 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (0.13 g, 0.55 mmol), and Cs2CO3 (0.19 g, 0.58 mmol) were suspended in DMSO (3.0 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copper iodide (0.13 g, 0.69 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH2Cl2, the resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (56 mg, 19%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.06-8.03 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 3.72-3.68 (m, 5H), 3.61-3.60 (m, 2H), 3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>COC1C=CC([Mg]Br)=C(C)C=1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:4]3[CH:27]=[CH:26][C:30]([O:29][CH3:28])=[CH:7][C:6]=3[CH3:15])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Agent: COc1ccc([Mg]Br)c(C)c1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c(C)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1.5 mL THF and 0.98 mL 0.5M 4-methoxy-2-methylphenylmagnesium bromide. Yield: 41 mg of a white solid. LC-MSD, m/z for C24H19BrN2O3 [M+H]+=463.0, 465.0; HPLC retention time: 2.4 min.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(Cl)Cl.C(N(CC)CC)C>>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:4][CH2:3][C@@H:2]([O:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl cis-4-hydroxycyclohexanecarboxylate (4.30 g, 25.0 mmol), p-toluenesulfonyl chloride (7.14 g, 37.4 mmol) and DCM (100 mL, 2000 mmol) was added triethylamine (6.96 mL, 49.9 mmol) at rt. The mixture was stirred at 25° C. overnight. The solution was transferred to a separatory funnel, washed with 2 M HCl to remove base, then washed with sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10-20% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ=1.16 (t, J=7.2 Hz, 3H), 1.52-1.67 (m, 8H), 2.31-2.40 (m, 1H), 2.42 (s, 3H), 4.05 (q, J=7.1 Hz, 2H), 4.66 (br. s., 1H), 7.47 (m, J=7.8 Hz, 2H), 7.80 (m, J=8.3 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[IH:11]>>[I:11][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: I
Reactant: Clc1ncnc2[nH]ccc12
Product: Ic1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (673 mg, 4.41 mmol) and 7 mL of 57% hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 5 mL of water and brought to pH=8 with aqueous ammonia solution. The suspension was cooled down to 0° C. and the solid was filtered off, washed with cold water and dried to give the product to yield 970 mg of the product as a white powder. The product contains about 10% of the starting material.