Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:10][CH2:11][CH2:12]2)[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: Nc1c(F)c(C2CCC2)nc(C=O)c1Cl
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(C2CCC2)nc(C(=O)O)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinaldehyde (209 mg, 0.914 mmol) and t-butanol (4.57 mL). The mixture was treated with water (1.523 mL), 2-methylbut-2-ene (0.8 mL, 0.914 mmol), sodium hydrogenphosphate (260 mg, 1.828 mmol), and finally sodium chlorite (248 mg, 2.74 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. After stiffing at room temperature overnight, an aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was triturated with Et2O and the Et2O removed giving 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinic acid (94 mg, 39.9%) as a yellow solid: 1H NMR (400 MHz, CDCl3) 11.60 (s, 1H), δ 4.94 (d, J=18.2 Hz, 2H), 3.86 (ttdd, J=9.1, 8.2, 2.1, 1.0 Hz, 1H), 2.35 (dddd, J=13.1, 6.9, 3.4, 1.8 Hz, 3H), 2.12 (m, 2H), 1.95 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −140.30; ESIMS m/z 243 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=2[N:17]=1.O1CCCC1>C(N(CC)CC)C>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[S:14][C:15]=2[CH:21]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(C(F)(F)F)cc2s1)c1c(F)cccc1F
Temperature: 35 °C
Reaction time: 5 h
Yield: 78.2 %

Procedure:
At 0 to 5° C., 2,6-difluorobenzoyl chloride (1.77 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), tetrahydrofuran (30 ml) and triethylamine (1.1 g). The reaction mixture was stirred at 30 to 40° C. for 5 hours, and then tetrahydrofuran was evaporated. The solid residue was washed with water and recrystallized from ethanol to give the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide (2.8 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([C:15]1[CH:53]=[CH:52][C:18]([CH2:19][C:20]2[C:21]([CH3:51])=[C:22]([OH:50])[CH:23]=[C:24]([C:26]3([O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]3[O:29][C:30](=[O:32])[CH3:31])[OH:27])[CH:25]=2)=[CH:17][CH:16]=1)[CH3:14].[CH:54]1(O)[CH2:57][CH2:56][CH2:55]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:54]1([O:50][C:22]2[CH:23]=[C:24]([C:26]3([O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]3[O:29][C:30](=[O:32])[CH3:31])[OH:27])[CH:25]=[C:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([CH2:13][CH3:14])=[CH:53][CH:52]=3)[C:21]=2[CH3:51])[CH2:57][CH2:56][CH2:55]1
Reactant: OC1CCC1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(O)c2C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC3CCC3)c2C)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (0.38 g) dissolved in THF (0.5 mL) is added to 3-(4-ethylbenzyl)-1-hydroxy-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.27 g), cyclobutanol (0.1 mL) and triphenylphosphine (0.56 g) dissolved in THF (2 mL). The mixture is heated with stirring at 70° C. overnight. After cooling to room temperature, the solvent is evaporated and the residue is purified by chromatography (cyclohexane/ethyl acetate 4:1->1:3) on silica gel.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[C:17](Cl)(=O)C>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([O:9][CH3:17])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.1 %

Procedure:
To an ice cooled stirred solution of 3-nitro-5-(trifluoromethyl)benzoic acid (25.00 g, 106.3 mmol) in methanol (500 mL) was added acetyl chloride (22.00 g, 280.2 mmol) dropwise over 20 min. After the addition was complete, the reaction mixture was stirred for 20 min at 0° C., then heated at reflux for 6 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, filtered through a silica gel and concentrated under reduced pressure to provide methyl 3-nitro-5-(trifluoromethyl)benzoate (24.65 g, 93%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>>[F:10][C:8]1[CH:9]=[C:2]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1Br
Product: O=Cc1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 92.8 %

Procedure:
2-bromo-4-fluorobenzaldehyde (1.53 g, 7.5 mmol) was reacted with (3,5-bis(trifluoromethyl)phenyl)boronic acid (2.3 g, 9 mmol) according to the procedure as described in Example 56, Step A to give the title compound as a white solid (2.34 g, 92%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:6]1.[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][N:27]([CH:28]([CH3:30])[CH3:29])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)=[O:25]
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Reactant: CC(C)=CCn1cc(C=CC(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (200.0 mg, 0.78 mmol), 3-fluoro-N′-isopropylbenzohydrazide (229.6 mg, 1.17 mmol) and HATU (444.9 mg, 1.17 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.2 ml, 1.17 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (50% EtOAc) and dried so that yellow (E)-3-fluoro-N′-isopropyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acroyl)benzohydrazide was obtained (286 mg, 88.2%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:12]=[S:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)Oc1cccc(N)c1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHC3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:27]3[CH2:28][CH2:29][CH2:30][CH:25]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=4)[C:26]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2Cl)cn1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2Cl)cn1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A suspension of [3-chloro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (66.7 mg, 0.25 mmol) and of 2-bromo-6-phenyl-cyclohexanone (63.3 mg, 0.25 mmol) in ethanol (4 mL) was stirred at room temperature for 30 minutes and then heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel with dichloromethane and then with dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (50 mg, 48%) as a pale-brown solid. MS ISP (m/e): 421.0/422.2 (100/38) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.38 (s, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.46-7.10 (m, 7H), 6.98 (s, 1H), 4.03 (m, 1H), 2.72 (m, 2H), 2.13 (s, 3H), 2.11 (m, 1H), 1.70-1.90 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1c(F)cccc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2c(F)cccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,6-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][CH:3]=[C:4]=[CH:5][CH2:6][CH3:7].Cl>C(O)CC.[OH-].[K+]>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH3:7]
Reactant: CCC=C=CCC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: CCC=CC=CC(=O)OCC
Yield: 92 %

Procedure:
20 g of the ethyl 3,4-heptadienoate obtained in Example 1 was agitated at 40°C. for 2 hours in 80 ml of propanol in the presence of 3 ml of 4N KOH as a catalyst. The resulting reaction mixture was neutralized with 4N HCl, dried and distilled. Ethyl 2,4-heptadienoate was obtained in a yield of 92% from a fraction boiling at 64.5°C. under 2.5 mm Hg. The double bond at the 2-position was of the trans-form and the double bond at the 4-position was composed of 55% of the cis-form and 45% of the trans-form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:14]3[CH:15]=[CH:16][O:12][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccoc1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccoc1
Yield: 49.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with 3-furaldehyde (1.04 mL, 11.9 mmol) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-furan-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.45 g, 55%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[C:7]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:23][CH3:24])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution (3 mL) of tert-butyl {[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (70 mg) in ethyl acetate was added 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (yield 29 mg, 49%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].O.[Cl-].[Na+]>N1C=CC=CC=1.Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]=2)[NH:13][CH:12]=1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Methanesulphonyl chloride (0.23 ml) was added to an ice cooled, stirred solution of 2-[2-[5-(aminomethyl)-1H-indole-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (0.84 g) in dry pyridine (25 ml). After 20 h at room temperature, a further portion of methanesulphonyl chloride (0.14 ml) was added. The mixture was stirred for 2 h, water (10 ml) was added and the solution was stirred for a further 1 h. The solution was diluted with hydrochloric acid (2N; 250 ml) containing sodium chloride (30 g) and ice. The product was extracted into ethyl acetate (2×80 ml) and the extract was washed with brine (2×60 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow foam (0.85 g).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:4][NH:5][CH:6]1[CH2:12][C:11]2[CH:13]=[C:14]([CH2:17][NH:18]C(=O)C)[CH:15]=[CH:16][C:10]=2[CH2:9][CH2:8][CH2:7]1.Cl>>[ClH:1].[ClH:1].[NH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:5][CH2:4][C@H:3]([OH:2])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:12][C:11]=2[CH:13]=1
Reactant: CC(=O)NCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Agent: Cl
Product: NCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Yield: 190.5 %

Procedure:
A mixture of N-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]methyl acetamide hydrochloride (100 mg) and 1N aqueous hydrochloric acid solution (2 ml) was heated to reflux for 18 hours. The solvent was removed under reduced pressure to dryness. The residue was triturated in diisopropyl ether, and the precipitated powder was collected by fIltration to afford (2S)-1-[(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol dihydrochloride (94 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]2[CH:13]=[N:14][N:15]=[C:11]2[C:10]2[CH:9]=[C:8]([CH3:16])[CH:7]=[CH:6][C:5]=2[N:4]=1.[OH-:17].[Na+].Cl>O1CCOCC1>[CH3:16][C:8]1[CH:7]=[CH:6][C:5]2[NH:4][C:3](=[O:17])[CH2:2][N:15]3[N:14]=[CH:13][N:12]=[C:11]3[C:10]=2[CH:9]=1
Reactant: [OH-]
Reactant: Cc1ccc2nc(CCl)n3cnnc3c2c1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)-c1ncnn1CC(=O)N2
Temperature: 8 °C
Reaction time: 0.17 h

Procedure:
5. 62.1 g of 5-(chloromethyl)-9-methyl-1,2,4-triazolo[4,3-c]quinazoline are suspended in 1.1 l of dioxan and cooled to 8° C. 320 ml of 1N sodium hydroxide solution are added dropwise thereto within 10 min. at 7° to 10° C. The mixture is stirred at room temperature for 24 h. The reaction mixture is then made weakly acid (pH 5-6) with 2N hydrochloric acid and concentrated in a vacuum. The residue is dissolved in dichloromethane and washed with sodium chloride solution. The organic phase is dried, decolorized with Norit charcoal, filtered clear and concentrated in a vacuum to a volume of about 400 ml. After the addition of 400 ml of ethyl acetate the mixture is again concentrated to a volume of about 200 ml. The crystal slurry is left to stand at -25° C. overnight and the crystals are then filtered off. After drying in a vacuum there are obtained 35.5 g of 10-methyl-5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 206°-208° C.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:41][C:36]1[CH:35]=[C:34]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH2:32][CH3:33])[CH:39]=[CH:38][C:37]=1[F:40]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Cl)c1

Procedure:
Compound 61 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-chloro-4-fluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [390 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.16 (s, 1H), 9.00 (d, 1H), 8.56 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 7.71 (dd, 1H), 7.52-7.43 (m, 1H), 7.35 (t, 1H), 5.44 (s, 1H), 3.16 (dd, 1H), 2.96 (dd, 1H), 2.57 (dt, 2H), 0.98 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15][CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:20]=[CH:19][N:18]=1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15]([CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:20]=[CH:19][N:18]=1)=[O:38])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)n1c(SCc2nccc(OCCCOC)c2C)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)n1c(S(=O)Cc2nccc(OCCCOC)c2C)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
0.6 g of 1-ethoxycarbonyl-2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthiobenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.4 g of m-chloroperbenzoic acid was added to the solution at -45° C. After one hour, 0.3 g of triethylamine and 20 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the resulting mixture. The obtained mixture was stirred at a room temperature for 30 minutes. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.21 g of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28](Cl)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC#N.CCOC(C)=O.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:1]2[CH2:4][CH:3]([CH2:5][O:6][C:7]3[C:16]([CH:17]4[CH2:19][CH2:18]4)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=3)[CH2:2]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CNC2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A mixture of methyl 4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (58 mg, 0.21 mmol), 1-chloro-4-(chloro(phenyl)methyl)benzene (74 mg, 0.31 mmol), potassium carbonate (86 mg, 0.62 mmol) and sodium iodide (32 mg, 0.21 mmol) in MeCN (10 mL) was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and brine (50 mL). The organic layer was separated and washed with brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with petroleum ether/EtOAc=4/1) to give the target compound (50 mg, 50%) as a pale yellow oil. LCMS (ESI) m/z: 480.1 [M+H].
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=O)[NH2:2].N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>O1CCOCC1>[C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)#[N:2]
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl (2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (Example 58, Step 2, 30 mg, 0.07 mmol) in dioxane (1.5 mL) was added pyridine (10.5 mg, 0.13 mmol) and TFAA (15.4 mg, 0.07 mmol). The reaction was kept at room temperature for 16 and additional pyridine (10.5 mg, 0.13 mmol) and TFAA (15.4 mg, 0.07 mmol) were added. After 5 h, the reaction was quenched by H2O and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded tert-butyl (2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (20 mg, 69% yield).