Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25].[OH-].[Na+]>N1C=CC=CC=1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH:20][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:21][CH:22]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CC(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 59.5 %

Procedure:
A solution of 1.5 g of 2-(4-carboxybenzamido)-4-aminobenzoic acid in 50 ml of pyridine was mixed with 3.2 g of isobutyroyl chloride and the mixture was heated at 50° to 60° C. for a period of 2 hours. The reaction mixture was further mixed with a solution of 4 g of sodium hydroxide in 20 ml of water and concentrated under vacuum. The residue was diluted with water and hydrochloric acid was used to adjust the pH of the dilution between 1 and 2. The precipitating crystal was filtered, washed with water and recrystallized from a solvent mixture of methanol and water to thereby produce 1.1 g of 2-(4-carboxybenzamido)-4-isobutyramidobenzoic acid having a melting point in the range of from 312° to 314° C. (decompose).
Reaction SMILES: O[C:2]1([CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1)[CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.ClCCl>[Na]>[CH2:3]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)[C:2]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1(Cc2ccsc2)C=CC=CC1
Agent: [Na]
Solvent: ClCCl
Product: c1ccc(Cc2ccsc2)cc1
Yield: 58.5 %

Procedure:
A solution containing P2I4 (3.42 g, 6 mmol) and 3-(1-hydroxybenzyl)thiophene (1.90 g, 10 mmol) in sodium-dried toluene (100 ml) was heated under nitrogen for one hour. The reaction mixture was cooled and then quenched with 10% aqueous sodium sulphite. The mixture was extracted with ether, and the combined organic phases were washed with water and brine then dried. Filtration and evaporation afforded a yellow oil, which on bulb-to-bulb distillation (110° C. at 0.05 mmHg) gave a pale-pink oil. Chromatography with dichloromethane gave 3-benzylthiophene as an oil (1.02 g, 53% yield); 1H nmr: delta 3.84 (2H,s), 7.0-7.2 (8H,m) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[F:20])=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].S([O:28][CH3:29])(OC)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[F:20])=[CH:9][C:29](=[O:28])[N:7]([CH3:8])[CH:6]=1)=[O:22])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(CC)cc1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(CC)cc1F
Temperature: 25 °C
Yield: 44.9 %

Procedure:
6-Chloro-4-(4-ethyl-2-fluoro-phenylamino)-nicotinic acid ethyl ester (23.0 g, 72.0 mmol) was dissolved in CHCl3 (200 mL) and the solution cooled (ice/water). Dimethyl sulfate (42.0 mL, 432.0 mmol) was added, the solution allowed to warm to room temperature then heated at reflux for 20 hours as in Example 1, alternate Step B to give 4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester as a white solid (10.30 g, 45%). 1H NMR [(CDCl3, 400 MHz] δ 9.17 (s, 1H), 8.19 (s, 1H), 7.23 (dd, J=10.1, 1.9 Hz, 1H), 6.99 (dd, J=8.3, 1.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.76 (s, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.52 (s, 3H), 2.64 (q, J=7.2 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H). (APCI+) calcd for C17H19FN2O3 318.34 (M+1), found 319.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][OH:24]>>[CH3:23][O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: CO
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[N+:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32]>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:31]([O-:33])=[O:32])[CH:39]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc([N+](=O)[O-])c1
Yield: 21.4 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-nitro-phenylboronic acid (43 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (12 mg, 22%). LC-MS m/e 432.31 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1ncc(C2(CNC(=O)c3cccc(F)c3Cl)CCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=364.1, tR (minutes, Method F)=1.95
Reaction SMILES: [CH3:1][C:2]1([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH2:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:19])[CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: CC1(Cc2cncnc2)C(=O)Nc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(Cc2cncnc2)C(=O)Nc2ccc(Br)cc21

Procedure:
3-Methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one (900 mg, 3.76 mmol) and N-bromosuccinimide (669 mg, 3.76 mmol) in N,N-dimethylformamide (20 mL) were stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC on Chiralpak AS, eluting with 25% isopropyl alcohol/CO2, to afford the enantiomers of 3-methyl-3-(pyrimidin-5-ylmethyl)-5-bromo-1,3-dihydro-2H-indol-2-one. Enantiomer A was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:33])[C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-chloro-4-(3-methylpiperazin-1-yl)phthalazine (3.64 g, 13.9 mmol) was dissolved in dry dichloromethane (30 mL) and triethylamine (4.26 mL, 30.6 mmol). Benzoyl chloride (1.77 mL, 15.3 mmol) was added and stirred at rt for 1 hour. The reaction was added to saturated NaHCO3 (150 mL) and the aqueous layer was extracted with 3× dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/30-100% ethyl acetate gave an off-white solid. MS (M+H)+=367.1.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([NH2:21])[CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([NH:21][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1sccc1-c1ccc([N+](=O)[O-])c(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(-c3ccsc3CO[Si](C)(C)C(C)(C)C)ccc2[N+](=O)[O-])cc1
Yield: 92.7 %

Procedure:
A solution of 91 (636 mg, 1.74 mmol) and 4-methoxybenzoyl chloride (446 mg, 2.62 mmol) in pyridine (10 ml) was stirred at room temperature during 16 h. The solvent was evaporated, ethyl acetate was added and washed with a saturated solution of NH4Cl and then with a saturated solution NaCl. The organic layer was dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 5-10% EtOAc in Hexanes), 804 mg (93%) of compound 92 was obtained as a yellow oil. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.64 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.95-7.93 (m, 3H), 7.59 (d, J=5.3 Hz, 1H), 7.46 (dd, J=8.6, 2.0 Hz, 1H), 7.28 (d, J=5.3 Hz, 1H), 7.10 (dt, J=9.0, 2.2 Hz, 2H), 4.95 (s, 2H), 3.85 (s, 3H), 0.88 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1>ClC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:24][CH2:25]2)[N:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Clc1cc(N2CCCCC2)nc(Cl)n1
Solvent: Clc1ccccc1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc(Cl)cc(N3CCCCC3)n2)CC1
Temperature: 140 °C

Procedure:
A mixture of 2,4-dichloro-6-(1-piperidinyl)pyrimidine (100 mg, 0.43 mmol) and 1-[3-(trifluoromethyl)pyrid-2-yl]piperazine (119 mg, 0.52 mmol) in chlorobenzene (1 mL) was heated at 140° C. in a sealed tube for 24 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (9:1). 4-chloro-6-(1-piperidinyl)-2-{4-[3-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl}pyrimidine was obtained as a solid (79 mg, 0.19 mmol, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.[H-].[Na+].[CH3:27]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:27])[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 62 %

Procedure:
6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved in N,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added, followed by stirring for 30 min under ice cooling. Methyl iodide (0.0107 ml) was added to the reaction solution, and the mixture was stirred under ice cooling for additional one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (32 mg, yield 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:23]3[C:24]([CH3:33])=[C:25]4[C:30](=[CH:31][CH:32]=3)[O:29][CH2:28][CH2:27][CH2:26]4)=[C:14]([CH2:21][OH:22])[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:23]3[C:24]([CH3:33])=[C:25]4[C:30](=[CH:31][CH:32]=3)[O:29][CH2:28][CH2:27][CH2:26]4)=[C:14]([CH:21]=[O:22])[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2c(CO)n(C)c(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(-c2c(C=O)n(C)c(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Yield: 86.1 %

Procedure:
To a solution of 7-Benzyloxy-3-hydroxymethyl-2-methyl-4-(5-methyl-chroman-6-yl)-2H-isoquinolin-1-one (3.5 g, 7.93 mmol) in dichloromethane (100 ml) was added manganese dioxide (6.89 g, 79.3 mmol). The resultant mixture was stirred at 70° C. under N2 for 2 h. The reaction mixture was filtered and concentrated to dryness to afford the title product (3.0 g, 86%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10]N)[CH:7]=[CH:8][CH:9]=1.[C:12]1(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C.C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:13]3[CH2:12][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:10][C:6]=2[CH:5]=1
Reactant: COc1cccc(NN)c1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c3c([nH]c2c1)-c1ccccc1C3
Temperature: 85 °C
Yield: 52.2 %

Procedure:
To a solution of 3-methoxyphenylhydrazine hydrochloride (3.65 g, 20.9 mmol) and 1-indanone (2.77 g, 21.0 mmol) in ethanol (11.8 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Orange precipitate began to form upon cooling, and the mixture was subsequently emerged in an ice water bath to further induce crystallization. The solid was collected by vacuum filtration and dissolved in 22 mL isopropanol. Sulfuric acid (36 N, 1.5 mL) was added via syringe, and the resulting solution was stirred at reflux (90° C.) for 16 hours. Upon cooling to room temperature, the solution was basified to pH 10 with aqueous sodium hydroxide (2% by mass) resulting in the formation of precipitate. The solid was collected by vacuum filtration to yield 29a as an orange solid (2.55 g, 10.9 mmol). Crude product was brought on to the next step without purification. For purposes of characterization, the product was purified by flash column chromatography (20:1 hexanes-ethyl acetate). 1H NMR (600 MHz, CDCl3): δ 8.18 (s, 1H), 7.50-7.52 (m, 2H), 7.40-7.41 (d, 1H, J=7.2 Hz), 7.30-7.32 (t, 1H, J=7.8 Hz), 7.16-7.19 (td, 1H, J=7.8, 1.2 Hz), 6.95 (d, 1H, J=2.4 Hz), 6.83-6.84 (dd, 1H, J=8.4, 2.4 Hz), 3.88 (s, 3H), 3.69 (s, 2H); 13C NMR (150 MHz, CDCl3): δ 156.2, 147.3, 142.3, 141.5, 135.3, 126.5, 125.3, 124.1, 121.9, 119.5, 119.4, 116.7, 109.6, 96.2, 55.7, 30.3. FTIR: cm−1 3399, 1612, 1405, 1255, 1155, 1041, 820. ESI-HRMS: Calcd. for C16H13NO+ [M]+: 235.0992, found 235.0990.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)=[N:10][C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Br:42]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:42][C:14]1[N:12]2[CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:21][CH:22]=3)=[N:10][C:11]2=[N:16][CH:15]=1
Reactant: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccc(F)cc5)cc4)CC3)n[nH]2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6ncc(Br)n6cc5-c5ccc(F)cc5)cc4)CC3)n[nH]2)n1
Yield: 65.2 %

Procedure:
133 mg (0.24 mmol) 6-(4-fluorophenyl)-7-(4-{4-[5-(6-methylpyridine-2-yl)-1H-[1,2,4]triazole-3-yl]-piperidine-1-ylmethyl}-phenyl)-imidazo[1,2-a]pyrimidine are dissolved in 2.5 mL chloroform. After addition of 65.2 mg (0.37 mmol) N-bromosuccinimide the reaction mixture is heated for three hours at reflux. The solvent is evaporated and the residue purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 97.5 mg (60.8%) of the desired product.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:16]([CH:18]([NH2:21])[CH2:19][CH3:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:21][CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:5]
Reactant: CCC(N)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.50 g of Boc-Pro-OH, 0.27 ml of 1-ethylpropylamine, 0.36 g of HOBT and 0.53 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 30 (Process 3) to give 324 mg of the title compound.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.Cl.[C:15]12([NH2:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C.C>C(O)C.[OH-].[Na+]>[C:15]12([NH:25][C:2]3[NH:7][C:6]4[CH:8]=[C:9]([Cl:11])[S:10][C:5]=4[S:4](=[O:13])(=[O:12])[N:3]=3)[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(NC23CC4CC(CC(C4)C2)C3)Nc2cc(Cl)sc21
Temperature: 120 °C
Reaction time: 41 h
Yield: 11 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), 1-adamantanamine hydrochloride (1.46 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 41 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (50 ml) followed by adjustment to pH <2 with 4M hydrochloric acid. The resulting dark mass was isolated by decantation and then partly dissolved in hot 1N sodium hydroxide (50 ml) followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 and the precipitate was filtered off and recrystallised from ethanol to give 160 mg (11%) of the title compound as a beige solid; mp 339-340° C.; 1H-NMR (DMSO-d6): δ1.64 (br s, 6H), 2.02 (br s, 6H), 2.06 (br s, 3H), 6.67 (br s, 1H), 7.10 (s, 1H), 10.55 (br s, 1H); MS: m/e 371/373 (M+); (C15H18ClN3O2S2) calc C, 48.44; H, 4.88; N, 11.30; found C, 48.27; H, 4.85; N, 11.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[N:14]=[C:13]([NH:22][C:23]3[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=3)[N:12]=[CH:11][C:10]=2[CH2:9]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:31][CH2:30][CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:13]2[N:12]=[CH:11][C:10]3[CH2:9][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15]=3[N:14]=2)[CH:24]=1)(=[O:42])=[O:41]
Reactant: OCCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (R)-2-(3-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol (4.59 g, 11.17 mmol) in dichloromethane (50 mL) was added triethylamine (2.33 mL, 16.75 mmol) and methanesulfonyl chloride (0.95 mL, 12.28 mmol). The mixture was stirred at room temperature for 1 h, washed with water (60 mL×3), dried over sodium sulfate and concentrated to yield the title compound as a yellow solid (5.37 g, 98% yield). 1H-NMR (DMSO-d6) δ 9.59 (s, 1 H), 8.37-8.35 (dd, 1 H), 8.33 (s, 1 H), 7.80 (s, 1 H), 7.71 (d, J=10.4 Hz, 1 H), 7.54-7.45 (m, 2 H), 7.29-7.22 (m, 3 H), 7.07-7.02 (m, 2 H), 6.82-6.78 (m, 2 H), 4.67 (t, J=6.8 Hz, 1 H), 4.45 (t, J=6.8 Hz, 2 H), 3.22-3.08 (m, 2 H), 3.13 (s, 3 H), 3.01 (t, J=6.4 Hz, 2 H). LCMS m/e 490 [M+H].
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH2:26])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
Propionyl chloride (2.02 mL, 23.1 mmol) and DIPEA (14.4 mL, 84.0 mL) were added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) in CH2Cl2 (195 mL). The mixture was stirred for 15 min at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl (2×), with aq. 1M NaOH (1×) and with brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→3:2) yielded the title compound (5.08 g, 71%). LC-MS: tR=1.09 min; ES+: 383.41.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C(O)CCC>[ClH:1].[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:3][CH2:4][CH2:5][CH3:6])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)CC1(CN)CCCCC1

Procedure:
A solution of 1aminomethyl-1-cyclohexane-acetic acid hydrochloride in n-butanol is saturated with hydrogen chloride at 0° C. The reaction mixture is then heated to 110° C for 2 hours while hydrogen chloride is passed through. The solution thus obtained is then evaporated at 60° C and the residue stirred up with hexane is filtered and dried. n-Butyl 1-aminomethyl-1-cyclohexane acetate hydrochloride is obtained in form of a white powder having a melting point of 106°-109° C.