Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]1[OH:50]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][C@H:38]4[OH:50])=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and tert-butyl(3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][CH2:21][CH2:22][Cl:23])[CH:6]=[CH:5]2
Reactant: ClCCCBr
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1c2ccc(Br)cc2ccn1CCCCl
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (Example 1b) (2 g) dissolved in NMP (20 mL) was treated with potassium carbonate (1.974 g) and 1-bromo-3-chloropropane (8.83 ml) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h. The cooled reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was dried (MgSO4), and evaporated. The residue was purified (SiO2 chromatography, elution with a mixture of DCM and isohexane) to give the subtitle compound (1.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH2:21][NH:22][CH3:23].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]([CH3:23])[CH2:21][C:13]1[N:12]([CH3:11])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:5]
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
A solution of 2-bromobenzoyl chloride (1.85 g, 8.45 mmole) in CH2Cl2 (10 mL) was added dropwise to a solution of 1-methyl-2-(methylaminomethyl)indole (1.47 g, 8.45 mmole) and Et3N (3.6 mL, 25.8 mmole) in CH2Cl2 (50 mL) at 0° C. The reaction was stirred at 0° C. for 15 min, then was allowed to warm to RT. After 2 hr, the mixture was concentrated in vacuo, and the residue was diluted with H2O. The mixture was extracted with Et2O, and the combined Et2O layers were dried (MgSO4) and concentrated in vacuo. The oily residue was triturated with Et2O/petroleum ether to afford the title compound (2.6 g, 87%) as a white solid: MS (ES) m/e 357 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>>[NH2:19][C:15]1[N:14]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:25]#[C:24][C:22]([CH3:23])([OH:26])[CH3:21])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH3:12])[CH:18]=[CH:17][N:16]=1
Reactant: CCOc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Reactant: C#CC(C)(C)O
Product: CCOc1nc2ccc(C#CC(C)(C)O)cc2n1-c1ccnc(N)n1

Procedure:
The title compound was prepared by the procedure described in Step 2 of Example 142-b by reacting 4-(6-bromo-2-ethoxy-1,3-benzodiazol-1-yl)pyrimidin-2-amine with 2-methyl-3-butyn-2-ol; 1H NMR (500 MHz, MeOD) delta 1.54 (3H, t, J=7.09 Hz), 1.58 (6H, s), 4.68 (2H, q, J=7.09 Hz), 7.11 (1H, d, J=5.67 Hz), 7.25-7.32 (1H, m), 7.39 (1H, d, J=8.20 Hz), 8.29 (1H, s), 8.31-8.43 (1H, m); LC-MS: m/z=+338.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH3:35])=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: CNCC(O)CO
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)CC(O)CO)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step G (0.370 g, 0.776 mmol), 3-methylamino-1,2-propanediol (0.098 g, 0.931 mmol), 1-hydroxy benzotriazole (0.115 g, 0.854 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.164 g, 0.854 mmol) were combined in amine-free N,N-dimethylformamide (3.9 mL), followed by addition of N,N-diisopropylethylamine (0.202 mL, 1.16 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with 1 N hydrochloric acid, 1 N sodium hydeoxide and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 5% of methanol in chloroform, to afford 0.400 g of the title compound as a white, crystalline solid, m.p.155-157° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[Si:22]([O:14][CH2:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[CH3:15])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 97.1 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 10.00 g of 2-benzyloxycarbonylamino-2-methylpropanol, 7.35 g of imidazole, 150 ml of anhydrous dimethylformamide and 8.14 g of t-butyldimethylsilyl chloride were used, to give 14.68 g of the title compound having an Rf value of 0.73 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Br)CC1
Temperature: 80 °C
Yield: 98 %

Procedure:
To a stirred solution of 2-bromobenzenethiol (1.0 g, 0.00529 mole) in DMF (10 mL) was added cesium carbonate (2.063 g, 0.0063 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.478 g, 0.00529 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with hexane to afford 1.93 g (98%) of 4-(2-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 372.06 (M+1)+, 92.78%. A solution of 4-(2-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (1.93 g, 0.0052 mole) in dioxane.HCl (3 mL), was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 1.38 g (99%) of 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride. 1H NMR (DMSO-d6): δ 9.1-8.9 (bs, 1H), 7.7-7.64 (d, 1H), 7.56-7.52 (d, 1H), 7.46-7.36 (t, 1H), 7.24-7.16 (t, 1H), 3.7-3.6 (m, 1H), 3.34-3.2 (bd, 3H), 3.1-2.94 (q, 2H), 2.16-2.04 (d, 2H), 1.84-1.66 (q, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CS(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A solution of 16.0 g (95 mmol) of 1-methylsulfanyl-4-nitro-benzene in 400 ml of DCM is mixed at room temperature with 24.6 g (100 mmol) of 3-chloroperoxybenzoic acid (about 70%). After 1 hour, the batch is diluted with DCM and washed with saturated NaHCO3 solution. The organic phase is dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 8:2). 7.6 g (41 mmol, corresponding to 43% of theory) of the product is obtained.
Reaction SMILES: C[O:2][C:3](OC)([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)COCCOCCO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:12]1([C:10]([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:2])=[O:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCOCCOCCO
Product: O=C(C(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 153.8 g (0.6 mole) of benzil dimethyl ketal, 90.1 g (0.6 mole) of triethylene glycol and 3.9 g of toluene-4-sulfonic acid monohydrate are heated to 75-85° C. under an aspirator vacuum (20-30 mbar). At about 63° C., everything is dissolved. The course of the reaction is monitored by thin-layer chromatography. The reaction is stopped as soon as less than 1% of benzil dimethyl ketal is present in the mixture or the amount of benzil formed is larger than the amount of benzil dimethyl ketal still present. This is the case after 2-3 hours. The yellow solution is then cooled and neutralized with 3.8 g of a 30% solution of sodium methylate in methanol. The mixture is then heated to 60° C. under an aspirator vacuum and the methanol is distilled off. The liquid residue is diluted with 500 ml of toluene, stirred with 10 g of activated carbon and filtered through a Hyflo bed. The filtrate is evaporated in vacuo. This gives 208.8 g of a yellow, viscous oil (photoinitiator no. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:36])=[O:35])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OC4C(F)=C(F)C(F)=C(F)C=4F)=[O:21])[CH:15]=3)[CH2:10]2)=[CH:4][CH:3]=1.[NH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O.C(OCC)(=O)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:35])=[O:36])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[NH:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)[CH:15]=3)[CH2:10]2)=[CH:39][CH:40]=1
Reactant: NN1CCCCC1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)NN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.07 cm3 of 1-aminopiperidine in 4 cm3 of dimethylformamide is stirred for 18 hours at room temperature. The mixture is taken up in 30 cm3 of ethyl acetate. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1-[bis-(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine is obtained melting at 175° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (400 MHz): 1.40 (2H, m, CH2), 1.60 (4H, m, 2CH2), 2.85 (4H, m, 2NCH2), 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m, 2CH arom.), 9.45 (1H, s, NH)].
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([I:15])=[CH:10][N:9]=1.BrCC(C)=C>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:1][C:2]([CH3:5])=[CH2:3])[C:11]([I:15])=[CH:10][N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc(Cl)ncc1I
Agent: C=C(C)CBr
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CNc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Potassium tert-butoxide (4.56 g, 40.73 mmol) was added to a stirred solution of 2-chloro-5-iodo-pyridin-4-ylamine (8.62 g, 33.94 mmol) in anhydrous THF (140 mL) and the mixture was stirred at room temperature for 0.25 h. 3-Bromo-2-methyl-propene (5.51 g, 40.73 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residues partitioned between DCM (100 mL) and water (100 mL). The organic layer was separated, the solvent removed in vacuo and the residues subjected to column chromatography on silica. Gradient elution with 5-20% EtOAc in petrol afforded the title compound (7.93 g, 76%) as a pale yellow oil. 1H NMR (DMSO-d6) 8.24 (1H, s), 6.50 (1H, br t), 6.39 (1H, s), 4.84 (1H, d), 4.73 (1H, d), 3.83 (2H, d), 1.70 (3H, s). MS: [M+H]+ 309.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([CH:6]=[CH2:1])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of n-butyllithium (4 mL, 2,5 M solution in hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added methyl 4-formylbenzoate (1.54 mL, 10 mmol) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The resulting precipitate was washed with ether, and the combined ethereal filtrates were washed with water until neutral and then dried over anhydrous MgSO4. The solvent was removed and the residue, 4-ethenyl-benzoic acid methyl ester, was used in the next reaction without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](CC(O)=O)[CH:8]=1>C(Cl)Cl.CN(C=O)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:1][C:2]([Cl:4])=[O:3])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (211 μl; 2.23 mmol; 1.2 eq.) was added to a suspension of 3-pyridineacetic acid (255 mg; 1.86 mmol; 1.0 eq.) in DCM/DMF (5 mL:3 μL) maintained at 0° C. under nitrogen atmosphere. The reaction mixture was then stirred at rt for 1 h. It was then concentrated under reduced pressure. The solid obtained was used as such in amidation reactions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6](Cl)=[N:5]2.[NH2:16][CH2:17][CH2:18][CH2:19][OH:20]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[N:5]2
Reactant: NCCCO
Reactant: Clc1nc2cc(Br)ccc2n2ccnc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(Br)ccc2n2ccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
To a solution of 7-bromo-4-chloro-imidazo[1,2-a]quinoxaline (2.75 g; 9.6 mmol; 1 eq) in anhydrous dioxane (421 mL), 3-aminopropanol (1.83 mL; 24.1 mmol; 2.5 eq) is added under argon atmosphere. After 17 hours of stirring under reflux, the reaction mixture is cooled to room temperature and diluted in ethyl acetate (250 mL). The organic phase is washed three times with a molar solution of sodium hydroxide (3×150 mL). The recombined water phases are extracted one more time with ethyl acetate (300 mL) and the combined organic phases dried over sodium sulfate and concentrated under vacuum. The resulting beige powder is further washed with ether (200 mL) to provide the title compound (2.70 g; 8.4 mmol; 89%) as a grey powder.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][C@H:47]([CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[CH2:48][OH:49].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][C@H:47]([CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[CH2:48][OH:49])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: N[C@@H](CO)C1CCCCC1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: OC[C@H](Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1)C1CCCCC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then (R)-2-amino-2-cyclohexylethanol (209 mg, 1.46 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 120° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol (18 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.38 (m, 1H), 8.09 (dd, J=1.0, 8.0 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.18-7.32 (m, 3H), 5.48 (s, 2H), 4.70 (br s, 1H), 3.72 (m, 1H), 3.50 (m, 2H), 1.54-1.77 (m, 6H), 0.94-1.23 (m, 5H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O=[C:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:26][CH:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: O=C1CC(C(=O)O)C1
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CC(Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (183 mg, 0.506 mmol) and 3-oxocyclobutanecarboxylic acid (63.5 mg, 0.557 mmol) in DCM (2.5 mL) and triethylamine (212 μl, 1.519 mmol) was added titanium(IV) chloride in DCM (0.759 ml, 0.759 mmol) at ambient temperature. The reaction mixture was concentrated, suspended in water, filtered, washed with water, and dried in a vacuum oven to give 3-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylic acid as yellow solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.4 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[CH2:8][C@H:7]([NH2:21])[C:6]1=[O:22].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[CH2:8][C@H:7]([N:21]=[CH:34][C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:6]1=[O:22]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COCC(=O)N1C[C@H](N)C(=O)N(CC(=O)OC)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COCC(=O)N1C[C@H](N=Cc2ccc3ccccc3c2)C(=O)N(CC(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of 638 (630 mg, 1.76 mmol) and 2-naphthylmethyl bromide (428 mg, 1.94 mmol) in CH3CN was added K2CO3 (608 mg, 4.4 mmol). The resulting mixture was stirred at ambient temperature. After 18 hours, the reaction mixture was diluted with CH2Cl2, washed with water then brine, dried over Na2SO4 then concentrated in vacuo. Flash chromatography (SiO2, 0 to 20% EtOAc/CH2Cl2) afforded 450 mg of 639.
Reaction SMILES: [CH3:1][C@@H:2]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])=[CH:17][CH:16]=1)[C:3](N1CCOCC1)=[O:4].C1C[O:39]CC1.[OH-].[Li+]>CO.O>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([C:21]2[N:20]([CH2:19][C:18]3[CH:34]=[CH:35][C:15](/[CH:14]=[CH:13]/[CH2:12][O:11][C@H:2]([CH3:1])[C:3]([OH:4])=[O:39])=[CH:16][CH:17]=3)[CH:24]=[CH:23][CH:22]=2)=[O:26])=[CH:32][CH:31]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2cccn2Cc2ccc(/C=C/CO[C@H](C)C(=O)N3CCOCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2cccn2Cc2ccc(/C=C/CO[C@H](C)C(=O)O)cc2)cc1
Yield: 85 %

Procedure:
The compound of Example 68-1 (213 mg, 0.45 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide (0.9 ml), followed by stirring under reflux for 7 hours. The reaction mixture was diluted with water and washed with diethyl water. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (155 mg, 85%).