Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:10]([F:20])[CH:9]=1)[CH2:4][CH3:5])[CH3:2].Br[CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:27]([NH:26][C:24]([CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:21])=[CH:9][C:10]=2[F:20])[CH2:15][CH2:16]1)=[O:25])[CH3:28]
Reactant: CCC(CC)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CCNC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(C(=O)NC(CC)CC)cc2F)CC1
Reaction time: 16 h
Yield: 33 %

Procedure:
A mixture of N-(1-ethyl-propyl)-3-fluoro-4-piperazin-1-yl-benzamide (12 mg, 0.04 mmol), 2-bromo-N-ethyl-2-phenyl-acetamide (12 mg, 0.05 mmol), and K2CO3 (8 mg, 0.05 mmol) in DMF (2 mL) was stirred for 16 h. The mixture was poured into water and extracted with DCM. The organic layer was dried (MgSO4) and purified by PTLC to give a white solid (6 mg, 34%). MS (ESI): mass calcd. for C26H35FN4O2, 454.58. m/z found, 455.5 [M+H]+. 1H NMR (CDCl3): 7.47-7.42 (m, 2H), 7.34-7.30 (m, 5H), 7.05-7.02 (m, 1H), 6.90 (t, J=8.4, 1H), 5.67 (d, J=8.9, 1H), 3.99-3.94 (m, 1H), 3.89 (s, 1H), 3.37-3.31 (m, 2H), 3.19-3.17 (m, 4H), 2.64-2.55 (m, 4H), 1.66-1.59 (m, 5H), 1.49-1.42 (m, 2H), 1.16 (t, J=7.2, 3H), 0.93 (t, J=7.4, 6H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C>Cl>[NH2:7][C@H:8]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](CC2CCCCC2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)CC2CCCCC2)CC1
Yield: 98 %

Procedure:
2.75 g (6.20 mmol) of the above-described (R)-{1-Cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester was stirred overnight in a mixture of 30 mL of peroxide-free dioxane and 30 mL of 6N aq. HCl. The resulting yellow mixture was concentrated to dryness on a rotary evaporator and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to yield the desired (R)-2-amino-3-cyclohexyl-1-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-1-one (2.10 g, 98% yield), which was characterized as its dihydrochloride salt by conversion with ethereal HCl to yield the white solid; mp=165–168° C.; MS (+) ESI m/z=346 (M+H)+.
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[F:8][C:9]1[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([O:18]C)=[N:11][CH:10]=1.O>C(#N)C.C(Cl)(Cl)Cl>[F:8][C:9]1[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([OH:18])=[N:11][CH:10]=1
Reactant: COc1ncc(F)nc1C(N)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.2 %

Procedure:
In a nitrogen atmosphere, 1.51 g of sodium iodide is dissolved in 22 mL of acetonitrile. Then, 1.10 g of trimethylsilyl chloride is added thereto. The resulting solution is stirred at ambient temperature for 20 minutes. Then, 0.43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide is added thereto. The resulting solution is stirred at the same temperature as above for 18 hours. Then, a mixture of 10 mL of water and 200 mL of chloroform is added to the reaction mixture, and separated into layers. The organic layer thus obtained is washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: hexane:ethyl acetate=2:1) to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]1[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:23])[CH2:15][CH2:14][CH:13]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1[F:32].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[CH2:35]([CH:15]1[CH2:14][CH:13]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=2[F:32])[CH:12]([CH3:11])[N:17]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:16]1=[O:23])[CH:34]=[CH2:33]
Reactant: CC1C(c2cc(F)cc(F)c2F)CCC(=O)N1CC(F)(F)F
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1CC(c2cc(F)cc(F)c2F)C(C)N(CC(F)(F)F)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled, stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.0 mL, 2.0 mmol) in THF (10 mL) at −78° C., was added a solution of (5S,6R & 5R,6S)-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (0.50 g, 1.54 mmol) in THF (10 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of allyl bromide (0.242 g, 2.0 mmol) in THF (10 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction was quenched by the addition of a saturated solution of sodium chloride (20 mL) and partitioned between water (50 mL) and EtOAc (200 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (50 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 40:60, to give the title compound. MS: m/z=366.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:11]=[C:10]2[C:6]=1[N:7](C)[CH:8]=[N:9]2)=[O:4].Cl.C(OCC)(=O)C>[OH-].[Na+]>[NH2:9][C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=1[NH:7][CH3:8]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc2ncn(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Yield: 53.7 %

Procedure:
2-(4-Chloro-2-fluoro-3-methoxyphenyl)-7-methyl-7H-purine-6-carboxylic acid methyl ester (200 mg, 0.57 mmol) was slurried in 2M sodium hydroxide (10 mL) and heated at reflux for 2 h. After cooling, the pH was adjusted to 4 with 1M HCl. The precipitated solid was dissolved by shaking the mixture with two portions of ethyl acetate (45 mL each). The combined organic phases were washed with brine, dried and evaporated to give the title compound (100 mg, 53% yield): 1HNMR (DMSO-d6) δ 7.62 (dd, 1H), 7.36 (dd, 1H), 7.05 (br s, 2H), 3.97 (m, 1H), 3.91 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:39]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[N:29]=[CH:30][CH:31]=[CH:32]4)(=[O:40])=[O:41])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc4cccnc34)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and quinoline-8-sulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 5.66 (s, 2H, 6.90 (d, J=2.0 Hz, 1H, 6,95-7.05 (m, 5H, 7.15-7.28 (m, 3H, 7.30-7.45 (m, 4H, 7.64 (t, J=7.8 Hz, 1H, 7.75 (dd, J=8.3, 4.1 Hz, 1H, 8.17 (dd, J=7.3, 1.3 Hz, 1H, 8.27 (dd, J=8.2, 1.2 Hz, 1H, 8.57 (dd, J=8.3, 1.7 Hz, 1H, 9.12 (dd, J=4.2, 1.6 Hz, 1H, 9.67 (s, 1H, 12.97 (br s, 1H; MS (ESI) m/z 534 (MH+); MS (ESI) m/z 532 [M-H]−; HRMS calcd for C31H24N3O4S: 534.1477; found (ESI+): 534.1481; Anal. calcd for C31H23N3O4S.0.25H2O: C, 69.19; H, 4.40; N, 7.81. Found: C, 69.28; H, 4.31; N, 7.73.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][N:30]=2)[CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][N:30]=2)[CH2:27][N:26]([S:10]([CH2:9][C@@:2]2([CH3:1])[NH:3][C:4](=[O:8])[NH:5][C:6]2=[O:7])(=[O:12])=[O:11])[CH2:25][CH2:24]3)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2cc3c(cn2)CNCC3)cc1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4ccc(Cl)cc4)ncc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.5 %

Procedure:
[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.086 g, 0.38 mmol) in anhydrous NMP (0.50 mL) was added dropwise to a stirred solution of 6-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,7-naphthyridine (0.046 g, 0.19 mmol), DIPEA (0.066 mL, 0.38 mmol) and anhydrous NMP (1.5 mL) at RT. After the addition was complete the solution was stirred at RT for 1.5 h, then diluted with water (1 mL) and purified by preparative HPLC to afford 0.0070 g (8%) of the title compound as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[O:14]1CCC[CH2:15]1.CN(C)C=O>CCCCCC>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][C:7]([CH3:11])([CH3:10])[C:8]#[C:9][CH:15]=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C#CC=O)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Yield: 78 %

Procedure:
To the solution of 10 g (50 mmol) of 3-(tert.butyldimethylsilyl)oxy-3-methyl-butyne in 25 ml. of anhydrous tetrahydrofuran cooled at -78° C. in an argon atmosphere was added dropwise over a 40 minute period 40 ml (0.64 mmol) 1.6M solution of N-butyl lithium in hexane, which was followed by addition of 31 ml (400 mmol) of N,N-dimethylformamide. The reaction mixture was stirred for an additional one-half hour at -78° C., and then quenched by addition of ice and pouring into 300 ml of brine. It was then extracted with pentane. The pentane extract was washed with saturated ammonium chloride solution, water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by distillation at 113°-115° C./25 mmHg. It gave 8.88 g (78%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O>CO>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CO
Product: Nc1cccc(C(=O)O)c1C(=O)O

Procedure:
A commercial sample of 3-nitrophthalic acid (20% 4-nitro by TLC) is dissolved in 150 ml. of hot water, filtered and cooled for 2 hours to give 13 g. of pure 3-nitrophthalic acid as a white solid. The recrystallized 3-nitrophthalic acid (13 g., 0.062 mole) is dissolved in methanol (200 ml.) and hydrogenated over platinic oxide (50 mg.) at 25 psi. When uptake ceases (one hour), the mixture is filtered and evaporated to 12.4 g. of solid 3-aminophthalic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1[nH]c(C(=O)NC2CN(c3cccc(C(=O)O)c3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 13 %

Procedure:
Ethyl 3-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)benzoate obtained in Example (223c) (84 mg, 0.22 mmol) was dissolved in methanol (2 mL). A 2 N aqueous lithium hydroxide solution (1.11 mL, 2.23 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution was added to the aqueous layer, followed by extraction with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 10 mg of the title compound as a white solid (13%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([O:17][CH2:18][CH3:19])=[CH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH2:9][CH2:8]1)C>[OH-].[Na+]>[CH2:18]([O:17][C:5](=[CH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH2:8][CH2:9]1)[C:4]([OH:20])=[O:3])[CH3:19]
Reactant: CCOC(=O)C(=CC1(c2ccccc2Cl)CC1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=CC1(c2ccccc2Cl)CC1)C(=O)O
Yield: 80.4 %

Procedure:
15.4 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid ethyl ester in 350 ml of 1 M sodium hydroxide solution (ethanol-water 2:1) is stirred for 24 hours at room temperature. Solvent is distilled off, residue is distributed between water and diethyl ether, water solution is acidified with 2N hydrochloric acid, and extracted with diethyl ether. After the organic phase is washed with water, dried (Na2SO4) and concentrated by evaporation, 11.2 g of the product is obtained.
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].CC(O)C>[CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1nc(C)cc(C(C)=O)n1
Reactant: C1COCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CC(C)O
Product: CCCCCCSc1nc(C)cc(C(C)N2CCOCC2)n1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
1-(2-Hexylsulfanyl-6-methyl-pyrimidin-4-yl)-ethanone (200 mg, 0.79 mmol) and morpholine (138 μL, 1.58 mol) were dissolved in tetraisopropyl orthotitanate (0.5 mL) and heated at 80° C. for 16 h. The brown solution was diluted with 2-propanol (5 mL) and treated with sodium cyanoborohydride (32 mg, 0.5 mmol) at 20° C. for 6 h. Extraction: 2×AcOEt, 2× sat. NH4Cl solution. Chromatography: Si-amine, heptane/ethyl acetate 85:15. One obtained 86 mg (34%) of a yellow oil. MS: m/z=324 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)[CH3:14]
Reactant: ClCc1ccc2[nH]nnc2c1
Reactant: CNC
Product: CN(C)Cc1ccc2[nH]nnc2c1
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 5-chloromethyl-1H-1,2,3-benzotriazole (Synth. Commun., (1993), 23, 2019) (1.34 g, 8.0 mmol) and dimethylamine (33% solution in ethanol, 10 mL) was heated in an autoclave at 100° C. for 12 hours. The solvent was removed under reduced pressure, and the residue was dissolved in saturated aqueous sodium bicarbonate. A continuous extraction using ethyl acetate was performed, and the resulting solution of the product was dried (MgSO4) and concentrated under reduced pressure to give 5-(N,N-dimethylaminomethyl)-1H-1,2,3-benzotriazole (890 mg, 63%) as a brown hygroscopic gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([N:18]([CH2:22][C@@H:23]([NH:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)C(=O)C)[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.C1COCC1.Cl.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:18][CH2:22][C@@H:23]([NH:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: COCc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NCCN2CCOCC2)C(C)=O)sc1-c1nc2ccncc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COCc1nc(NC[C@H](Cc2ccc(C(F)(F)F)cc2)NCCN2CCOCC2)sc1-c1nc2ccncc2s1
Temperature: 150 °C
Yield: 6.7 %

Procedure:
A glass microwave reaction vessel was charged with N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)-N—((S)-2-(2-morpholinoethylamino)-3-(4-(trifluoromethyl)phenyl)propyl)acetamide (0.111 g, 0.2 mmol), THF (2.0 mL, 24 mmol), and HCl (2.0 mL, 10 mmol). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 12 minutes. The mixture was then made basic with NaOH, extracted with EtOAc, and the organics were adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to provide the title compound, 4-(methoxymethyl)-N—((S)-2-(2-morpholinoethylamino)-3-(4-(trifluoromethyl)phenyl)propyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine (0.008 g, 8% yield). LCMS (M+H) 593.2 calc. for C27H32F3N6O2S2 593.20. 1H NMR (400 MHz, CD3OD): δ ppm 9.13 (s, 1H), 8.50 (d, J=5.7 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 4.69 (s, 2H), 3.50 (s, 3H), 3.47 (m, 6H), 3.14 (m, 1H), 2.95 (dd, J=6.0, 13.6 Hz, 1H), 2.84 (dd, J=7.9, 13.6 Hz, 1H), 2.77 (dd, J=5.8, 11.9 Hz, 1H), 2.68 (m, 1H), 2.40 (m, 2H), 2.29 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([F:13])[C:3]=1[C:4]([NH:6][OH:7])=[NH:5].CO[C:16](OC)(N(C)C)[CH3:17]>CC(O)C>[Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([F:13])[C:3]=1[C:4]1[N:5]=[C:16]([CH3:17])[O:7][N:6]=1
Reactant: N=C(NO)c1c(F)cc(Cl)cc1Br
Reactant: COC(C)(OC)N(C)C
Solvent: CC(C)O
Product: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-N-hydroxy-benzamidine (26.5 g, 99.25 mmol) in 2-propanol (200 ml) was added N,N-dimethylacetamide dimethyl acetal (35.2 ml, 238.20 mmol) slowly at 25° C. and the reaction mixture was stirred for 30 minutes. After completion of the reaction all volatiles were evaporated and the resulting crude product was purified by chromatography (silica gel; hexane/EtOAc 97:3) to obtain the title compound (27.5 g, 58%) as white solid. MS: 290 (M+, 1Br).
Reaction SMILES: Br.[O:2]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[NH:9])[CH2:4][CH2:3]1.C(O)C.[C:14]([CH2:17][C:18](=O)[CH3:19])(=O)[CH3:15]>>[CH3:15][C:14]1[CH:17]=[C:18]([CH3:19])[N:10]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[N:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: N=C(N)N1CCOCC1
Agent: Br
Solvent: CCO
Product: Cc1cc(C)nc(N2CCOCC2)n1
Temperature: 140 °C
Yield: 89.7 %

Procedure:
To a suspension of morpholinoformamidine hydrobromide (2.0 g, 9.52 mmol) in ethanol (6 ml) potassium tert-butoxide (1.068 g, 9.52 mmol) then acetylacetone (2 ml, 20 mmol) were added. The reaction mixture was flashed with argon, sealed in the Emrys process vial and heated under microwave irradiation at 140° C. for 5 min. After cooling it was quenched with ethyl acetate (50 ml), filtered via plug of SiO2 (5 g) and eluted with ethyl acetate. Volatiles were removed in vacuo at 70° C. to furnish 1.65 g of pale brown oil that solidified overnight. Yield 90%. LC-MS (m/z) 193.9 (MH+); tR=0.71. 1H NMR (500 MHz, DMSO-d6): 2.23 (s, 6H), 3.62 (m, 4H), 3.67 (m, 4H), 6.44 (s, 1H).
Reaction SMILES: [OH-].[Li+].[C:3]1([CH3:22])[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])[CH:4]=1>CO.O>[C:3]1([CH3:22])[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])[CH:4]=1
Reactant: COC(=O)c1ccc(C(C)Oc2cccc(C)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(OC(C)c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Lithium hydroxide (54 mg, 2.2 mmol) was added to a solution of methyl 4-(1-(m-tolyloxy)ethyl)benzoate (148 mg, 0.55 mmol) in methanol (100 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was removed in vacuo. 3 mol/L aqueous hydrogen chloride was added to make pH 2-3, and the product was extracted with dichloromethane (100 mL*3) The combined organic phase was washed with sodium Chloride (20 mL*3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4-(1-(m-tolyloxy)ethyl)benzoic acid (124 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:17])=[C:7]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:7]2[C:8](=[N:9][C:10]3[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:6]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(C)c3c(nc2c1)CCNCC3
Product: CCOC(=O)N1CCc2nc3cc(C)ccc3c(C)c2CC1
Yield: 79 %

Procedure:
8,11-Dimethyl-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 8,11-dimethyl-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155. Yield: 79% of theory; m.p. 121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of (3-hydroxy-benzyl)-carbamic acid tert-butyl ester (250 mg, 1.12 mmol), 2-fluoro-5-nitro-pyridine (150 mg, 1.12 mmol) and K2CO3 (120 mg) in N,N-dimethylformamide (3 mL) was heated under microwave condition at 100° C. for 10 min. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (7:1) to give the title compound (165 mg, 43%). MS (DCI/NH3) m/z 346 (M+1)+.