Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[CH2:1]([C:3]1[C:4]([O:13][CH2:23][O:24][CH3:25])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCc1ccc(C)c(C(=O)O)c1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C)c(C(=O)O)c1OCOC
Reaction time: 8 h
Yield: 111.7 %

Procedure:
A solution of ethyl 2-hydroxy-6-methylbenzoic acid (4.56 g, 25.3 mmol) and diisopropylethylamine (13.2 ml, 76 mmol) in dry dichloromethane (30 ml) was cooled in an ice-bath. Chloromethyl methyl ether (3.83 ml, 50.6 mmol) was added slowly and the mixture was allowed stand at 0° C., warning slowly to room temperature. After 36 h a further portion of chloromethyl methyl ether (1.9 ml) was added and the mixture was left at room temperature overnight. The mixture was then washed with 10% citric acid, water and brine, dried and evaporated to give the title compound (6.34 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41](Br)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])[CH:25]=1.CN(C=O)C>CCOCC.[Cu]I.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>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:36]=2)=[O:34])[CH3:31])[CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1cccnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)c1cccnc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
6-Chloro-3-tributylstannyl-1H-indazole (584 mg, 1.32 mmol), copper(I) iodide (14 mg, 0.074 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide (350 mg, 0.74 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with nitrogen for 10 min then tetrakis(triphenylphosphine)palladium (0) (42 mg, 0.037 mmol) was added and the reaction was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 203 mg (48%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=549.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[Cu](C#N)[C:10]#[N:11].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)nn1
Reactant: N#C[Cu]C#N
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(Cl)nn1
Yield: 89 %

Procedure:
A mixture of 3-chloro-6-iodo-pyridazine (CAS 135034-10-5, 5.5 g, 22.9 mmol; Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron (1999), 55 (52), 15067-15070) and copper cyanide (4 g, 44.7 mmol) in acetonitrile (30 ml) was stirred for 30 min. at 160° C., under microwave irradiation (Milestone MW-oven). The mixture was then poured into dichloromethane (200 ml), filtered over celite, and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane/heptane 1:1 to 7:3) to yield D4 (2.84 g, 89%), as a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[CH:15]=[C:16]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:18][C:13]=3[C:12]3[C:7](=[CH:8][N:9]=[CH:10][CH:11]=3)[C:6]2=[O:34])[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]2[C:12]3[C:7](=[CH:8][N:9]=[CH:10][CH:11]=3)[C:6](=[O:34])[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:14]=2[CH:15]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(CC3CC3)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-(cyclopropylmethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.08 g, 0.172 mmol) in anhydrous methanol (5 mL) was added a 4M solution of HCl in 1,4-dioxane (2 mL, 65.8 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (10 mM ammonium acetate in water:acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one (22 mg, 0.060 mmol, 35% yield) as a yellow gum. LC/MS (ESI) m/e 366.2 [(M+H)+, calcd for C22H28N3O2 366.2]; LC/MS retention time (method A): tR=1.47 min; HPLC retention time (method A): tR=9.470 min; HPLC retention time (method B): tR=5.250 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.47 (d, J=0.50 Hz, 1H), 8.78 (d, J=5.77 Hz, 1H), 8.46 (d, J=9.04 Hz, 1H), 8.26 (d, J=5.52 Hz, 1H), 7.28 (d, J=2.26 Hz, 1H), 7.14 (dd, J=9.03, 2.26 Hz, 1H), 4.39 (d, J=6.78 Hz, 2H), 4.31 (dd, J=9.79, 3.76 Hz, 1H), 4.13 (dd, J=9.79, 6.78 Hz, 1H), 3.53 (dd, J=7.15, 3.64 Hz, 1H), 1.87 (m, 1H), 1.59 (q, J=13.72, 7.03 Hz, 2H), 1.36-1.45 (m, 1H), 1.04 (dd, J=7.28, 6.78 Hz, 6H), 0.57-0.63 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]2([OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]2=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:26][C:27]1C=C2C(=C[CH:35]=1)N(CCC1C=CC=CC=1)C(=O)C2=O.CC1C=CC=CN=1>>[OH:25][C:9]1([CH2:8][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]([CH2:19][CH2:20][C:21]2[CH:23]=[CH:35][CH:27]=[CH:26][CH:22]=2)[C:10]1=[O:24]
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCc1ccccc1
Solvent: Cc1ccccn1
Product: Cc1ccc2c(c1)C(O)(Cc1ccccn1)C(=O)N2CCc1ccccc1

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-methyl-1-phenethylindoline-2,3-dione and 2-methylpyridine (purchased from Fisher Scientific). 1H-NMR δ 8.6 (d, 1H), 7.65 (m, 1H), 7.27 (m, 6H), 7.05 (d, 1H), 6.98 (d, 1H), 6.71 (m, 2H), 4.6 (bs, OH), 3.5 (m, 1H), 3.8 (m, 1H), 3.1 (m, 2H), 2.95 (m, 2H), 2.21 (s, 3H). Calculated mass for C23H22N2O2, 358.17. Observed 359.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CN1CCNCC1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Product: CCCOc1ccc(CN2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
The title compound was prepared form 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one and 1-methylpiperazine, following the procedure of Example 34, and was obtained as a colourless solid (36%), m.p. 149°-150° C. Found C,65.68; H,7.83; N,19.10. C24H34N6O2 requires C,65.73; H,7.81; N,19.16%
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[C:17]([NH2:19])=[O:18])[CH3:12].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:19]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:12]
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccccc3)co2)cc1OCC
Temperature: 170 °C
Yield: 16.9 %

Procedure:
In a microwave vial were dissolved 2-bromo-1-phenylethanone (95 mg, 0.478 mmol) and 3,4-diethoxybenzamide (100 mg, 0.478 mmol) in DMF (5 ml) and the reaction was heated at 170° C. for 40 min. The reaction mixture was poured in a saturated solution of NaHCO3 and extracted with EtOAc (50 ml×3). The combined organic phases were washed with a saturated solution of NaCl (30 ml×2) and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (95:5) to yield 25 mg (17%) of the product. MS (EI) m/z: 310 (M+)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(Cl)c2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2cccc(Cl)c2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@@H:11]2[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1>C(Cl)Cl>[Cl:23][C:21]1[C:20]([Cl:24])=[CH:19][C:9]2[N:10]([C@@H:11]3[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:7][C:8]=2[CH:22]=1
Reactant: CC(C)N
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 90.4 %

Procedure:
Following General Procedure V, isopropylamine (Aldrich, 3 mL, 34.92 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (200 mg, 0.52 mmol) were reacted for 16 h. Purification on a silica gel column with 1:15 methanol:CH2Cl2 gave 5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (168 mg, 0.47 mmol, 90%); MS (EI): m/z (rel. intensity) 360 (0.17, M+); 1H NMR (DMSO-d6) δ7.41 (s, 1H, Ar—H), 7.32 (s,1H, Ar—H), 6.63 (d; 1H, NH, J=7.3 Hz), 5.73 (d, 1H, CH, J=6.6 Hz), 5.26 (m, 2H, 2 overlapping OH), 4.33 (m, 1H, CH), 4.01 (m, 1H, CH), 3.91 (m, 1H, CH), 3.81 (m, 1H, CH), 1.37 (d, 3H, CH3, J=6.1 Hz), 1.21 (d, 6H, CH3, J=6.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1.Cl.C(O)(C)C.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O1CCOCC1>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (165 mg, 0.000659 mol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (220 mg, 0.00066 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and Isopropyl alcohol (6.6 mL, 0.086 mol;) were combined in a microwave vessel. Heat at 130° C. for 20 min. The mixture was treated with 500 mgs of MP-carbonate resin and stirred for 20 min. The mixture was filtered and concentrated and put on high vac overnight. The crude solid was dissolved in DCM and purified on an ISCO column (40 g, SiO2, 100% DCM to MeOH/DCM gradient) to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonam (99 mg, 48%). MP: 92-94° C. 1H-NMR (CDCl3, 400 MHz): 1H-NMR (CDCL3) δ 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.37-5.31 (m, 2H), 3.99-3.95 (broad m, 1H), 3.88 (s, 1H), 3.56 (br s, 2H), 3.38 (s, 1H), 3.28-3.24 (m, 1H), 2.99-2.70 (complex series of m, 11H), 2.26-2.20 (m, 2H), 1.88-1.80 (m, 2H), 1.41-1.28 (m, 6H), 0.92-0.85 (m, 2H); LC/MS: 552.92 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:13][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc2[nH]ccc12
Reaction time: 3 h
Yield: 94.7 %

Procedure:
1H-Indole-4-carbaldehyde (219 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to an orange solid and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.0 mg, 1.53 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (1H-indol-4-ylmethyl)-methyl-amine (229 mg, 94%) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1H), 7.29-7.24 (m, 2H), 7.03-6.93 (m, 2H), 6.51-6.50 (m, 1H), 3.88 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27]([OH:29])=O)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH3:36][NH:37][O:38][CH3:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:29])[N:37]([O:38][CH3:39])[CH3:36])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CNOC
Reactant: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)N(C)OC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 34.9 %

Procedure:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (4 g, 7.2 mmol) was reacted with N,O-dimethylhydroxylamine hydrochloride (0.84 g, 8.64 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (1.5 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:26]=[O:28])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Temperature: 75 °C
Yield: 72.3 %

Procedure:
To a mixture of 6-(4-amino-phenoxy)hexanoic acid methyl ester 21 (26 grams, 109.7 mmol) and triethylamine (29.2 g, 288.56 mmol) in toluene (390 ml) under nitrogen atm. was added triphosgene (15.6 grams, 52.56 mmol) in one lot. The reaction was exothermic and the internal temperature rose to 60° C. Later, the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered, and the toluene was distilled off under vacuum to get crude 36, which was vacuum distilled to get pure 36 (10 g, 34.7%). M.p: 47-50° C.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:17][CH2:18][C:19](O)=O>>[Cl:17][CH2:18][C:19]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=1
Reactant: Nc1ccccc1NCCc1ccccc1
Reactant: O=C(O)CCl
Product: ClCc1nc2ccccc2n1CCc1ccccc1
Yield: 61.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-phenethylbenzene-1,2-diamine (2.57 g, 12.11 mmol) and 2-chloroacetic acid (0.70 g, 18 mmol). The crude residue was purified over silicagel chromatography prepacked 70 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.02 g of 2-(chloromethyl)-1-phenethyl-1H-benzo[d]imidazole (Yield: 61%) as a white crystalline solid.
Reaction SMILES: [CH3:1]NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]5[CH:31]=[CH:30][NH:29][N:28]=5)=[CH:25][N:26]=4)[CH:23]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][C:10]=1[F:11].FC1C=CC(C2C(C3C=C4C(=CC=3)N(C(N3C5C(=CC(C6C(C7C=CC(F)=C(C)C=7)=NC=CC=6)=CC=5)C=N3)=O)N=C4)=CC=CN=2)=CC=1C>>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]5[CH:31]=[CH:30][N:29]([CH3:1])[N:28]=5)=[CH:25][N:26]=4)[CH:23]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Fc1ccc(-c2ncccc2-c2ccc3ncc(-c4cc[nH]n4)n3c2)cc1Cl
Reactant: CNN
Agent: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)n3ncc4cc(-c5cccnc5-c5ccc(F)c(C)c5)ccc43)c2)ccc1F
Product: Cn1ccc(-c2cnc3ccc(-c4cccnc4-c4ccc(F)c(Cl)c4)cn23)n1

Procedure:
6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine was prepared by the reaction of MeNHNH2 and enamine, analogous to the preparation of 6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine. 1H NMR (300 MHz, DMSO-d6): δ 8.74 (dd, J=4.8, 1.6 Hz, 1H), 8.43 (dd, J=1.7, 0.9 Hz, 1H), 8.42 (s, 1H), 8.04 (dd, J=7.8, 1.6 Hz, 1H), 7.89 (dd, J=9.4, 0.8 Hz, 1H), 7.73 (dt, J=8.1, 1.1 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.56 (dd, J=7.8, 4.8 Hz, 1H), 7.51 (dd, J=9.3, 1.6 Hz, 1H), 7.31-7.21 (m, 2H), 6.74 (d, J=2.0 Hz, 1H), 3.82 (s, 3H). 19F NMR (282 MHz, DMSO-d6): δ −116.76 (q, J=7.3 Hz). LCMS: rt 5.09 min (A), purity 99%, MS (m/e) 404 MH+.
Reaction SMILES: IC.[Cl:3][C:4]1[C:5]([C:18]([OH:20])=[O:19])=[N:6][CH:7]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][O:19][C:18]([C:5]1[C:4]([Cl:3])=[CH:9][C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ncc(COc2ccccc2)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(COc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
Iodomethane (0.4 mL, 6.39 mmol) was added to a suspension of 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid (265 mg, 1.92 mmol) and K2CO3 (265 mg, 1.92 mmol) in DMF (15 mL) in a sealed tube. The mixture was stirred at RT for 16 h. The solvent was evaporated in vacuo and the mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (258 mg, 73%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=1)=[N:30][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CC(C)N
Product: CC(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 45 %

Procedure:
N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and isopropylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was crystallized from ethyl acetate and heptane to give the title compound (114 mg, 45%) as white crystals. Mp 176-182° C.; 1H-NMR (CDCl3): δ 1.25 (d, 6H), 4.07 (m, 1H), 5.5 (br d, 1H), 7.71 (br s, 1H), 7.75 (br s, 2H), 8.10 ppm (br, 1H); MA calc for C13H12F6N4 : C, 46.16%; H, 3.58%; N, 16.56%. Found: C, 46.15%; H, 3.64%; N, 16.45%.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=1)[O:12][C:11]([CH3:20])([CH3:19])[CH:10]=[C:9]2[C:21]([OH:24])([CH3:23])[CH3:22].O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH2:17]([O:16][C:14]1[CH:15]=[C:6]([CH:2]=[O:1])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:20])([CH3:19])[CH:10]=[C:9]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH3:18]
Reactant: CCOc1cc(C2OCCO2)cc2c1OC(C)(C)C=C2C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CCOc1cc(C=O)cc2c1OC(C)(C)C=C2C(C)(C)O
Reaction time: 0.25 h

Procedure:
The above prepared 2-(6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl)-propan-2-ol was dissolved in 6 ml of methanol and 3 ml of water and treated with 54 mg of pyridinium p-toluenesulfonate. After 15 min. at room temperature, the reaction mixture was poured onto crushed ice/AcOEt, the organic layer washed with water, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2 with n-hexane/AcOEt=7/3) yielded 194 mg of the title compound as colourless oil.