Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC(O)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
step 1—To a solution of 1,4-cyclohexanediol (20.0 g, 172 mmol) and pyridine (100 mL) cooled to 0° C. was added dropwise over 2 h a solution of 32.0 g (168 mmol)p-toluenesulfonyl chloride in CHCl3 (100 mL). After the addition was complete the reaction mixture was stirred at RT for 17 h. The solvent was evaporated in vacuo and the residue was taken up in refluxing toluene and petroleum ether was added until the solution became cloudy. The mixture was cooled and the supernatant was decanted. The remaining solid was dissolved in DCM and vacuum filtered through a pad of SiO2. The filter cake was washed with a mixture of DCM/MeOH (95:5). The dark golden oil was dried under vacuum to afford 35.6 g (78%) of toluene-4-sulfonic acid 4-hydroxy-cyclohexyl ester (76) contaminated with a small amount of bis-tosylate: 1H NMR (CDCl3, 300 MHz): δ 7.79 (dd, 2H), 7.73 (dd, 2H), 4.64-4.48 (m, 1H), 3.75-3.69 (m, 1H), 2.45 (s, 3H), 1.95-1.83 (m, 3H), 1.70-1.26 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:17]([CH3:19])[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:17]([CH3:19])[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Cc1nc(C2CN(c3cc(Cl)nc(N)n3)CCO2)[nH]c1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc(C2CN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)CCO2)[nH]c1-c1ccccc1
Yield: 81.3 %

Procedure:
A mixture of 4-chloro-6-[2-(4-methyl-5-phenyl-1H-imidazol-2-yl)-4-morpholinyl]-2-pyrimidinamine (1.2 g, 3.24 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.199 g, 4.85 mmol), Na2CO3 (0.857 g, 8.09 mmol) and Pd(PPh3)4 (0.374 g, 0.324 mmol) was placed into a microwave vial and heated in Biotage Initiator using initial 150 W to 140° C. for 1 hour. After cooling the reaction, the solvent was removed under reduced pressure, and the crude product was added to a silica gel column and eluted with Hex/EtOAc (1:3) to afford the title compound (1.2 g) as a yellow solid. LC-MS (ES) m/z=456 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=5)[C:6]=4[CH:16]=3)=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: Brc1ccc2ncn(-c3ccncc3)c2c1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: Clc1ccc(-n2nccc2-c2ccc3ncn(-c4ccncc4)c3c2)cc1

Procedure:
The title compound, white solid (50 mg, 37%), MS (ISP) m/z=372.4 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-pyridin-4-yl-1H-benzoimidazole (intermediate L) (100 mg, 365 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (97.4 mg, 438 μmol).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[CH:9]=1)[CH:4]([CH3:6])[CH3:5].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:17]1[CH2:18][CH2:19][N:14]([C:10]2[CH:9]=[C:8]([O:7][CH2:3][CH:4]([CH3:6])[CH3:5])[N:13]=[CH:12][N:11]=2)[CH2:15][C:16]1=[O:20]
Reactant: CC(C)COc1cc(N2CCNC(=O)C2)ncn1
Reactant: ClCc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(N2CCN(Cc3nc4ccccc4o3)C(=O)C2)ncn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 2.8 mg, 0.07 mmol) in DMF was added 4-(6-isobutoxypyrimidin-4-yl)piperazin-2-one (16 mg, 0.064 mmol). After 5 min, 2-(chloromethyl)benzo[d]oxazole (10.7 mg, 0.064 mmol) was added, and the mixture was stirred at rt for 30 min. The mixture was quenched with water, extracted with EtOAc (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 9.3 mg (38% yields) of the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:37]([Si:41]([CH3:44])([CH3:43])Cl)([CH3:40])([CH3:39])[CH3:38].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1COCC1.CO>[C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([O:29][Si:41]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:44])[CH3:43])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC

Procedure:
In analogy with Example 44e), 1.526 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4,5-trimethoxyphenyl)methyl]hexanoic acid in 15.16 ml of DMF are silylated with 2.11 g of tert-butyldimethylchlorosilane and 1.683 g of imidazole. The silyl ester group in the crude product is detached, at RT in 2.5 h, in a mixture consisting of 40.3 ml of methanol, 13.8 ml of THF, 13.8 ml of water and 2.42 g of potassium carbonate. The title compound is purified by being chromatographed twice on silica gel (solvents: hexane, C and J). TLC Rf (A)=0.39. FAB-MS (M+H)+ =618.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCCC1.O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)#[N:10]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)c(Oc2ccccc2)nc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
2,3-Dicyano-5,6-dichloropyrazine (1.00 g; 0.005 mole) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to -15° to -10° C. A solution of 0.47 g (0.005 mole) of phenol and 0.21 g (0.005 mole) of sodium hydroxide in 25 ml of water was added dropwise over the period of 30 minutes. The mixture was stirred at -15° to -10° C. for 1 hour. The reaction mixture was poured into 100 ml of ice water, and the precipitate was collected by filtration. The precipitate was dissolved in 50 ml of chloroform, washed with 20 ml of a dilute aqueous solution of sodium hydroxide and 30 ml of water, dried over anhydrous calcium chloride, and concentrated under reduced pressure. The crude product was chromatographed on a column containing 60 g of silica gel using benzene as an eluent to afford 0.65 g (yield 50%) of 2,3-dicyano-5-chloro-6-phenoxypyrazine.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.23 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (2,17 mL, 18.23 mmol) was added and the solution was further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 1.88 g (42%) of white solids. M.P. 95° C. 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.26 (m, 2H), 7.35 (m, 5H), 7.40 (m, 2H), 7.64 (dt, J=2.9, 8.4 Hz, 1H), 7.82 (dd, J=3.2, 8.0 Hz, 1H). Anal. (C16H13NO3) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:27])[C:8]2[O:14][C:13]3[C:15]([Cl:23])=[CH:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[CH:18][C:12]=3[CH2:11][S:10](=[O:25])(=[O:24])[C:9]=2[CH:26]=1)=[O:4].[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:27])[C:8]2[O:14][C:13]3[C:15]([Cl:23])=[CH:16][C:17]([N:19]([C:30](=[O:31])[CH2:29][Cl:28])[CH2:20][CH2:21][Cl:22])=[CH:18][C:12]=3[CH2:11][S:10](=[O:24])(=[O:25])[C:9]=2[CH:26]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
4-Chloro-2-(2-chloro-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid methyl ester (prepared by following the method described in example 29a or example 29b, 1.9 gm, 4.4 mmol) was added to chloroacetyl chloride (6 mL) at room temperature. Reaction mixture was then stirred at 90° C. for 1 h. Reaction mixture was cooled and diluted using ice water (100 mL). The solid separated was filtered, washed with water and dried to obtain the title compound. Yield: 1.85 g, (83%); 1H NMR (DMSO-d6, 300 MHz): δ 2.60 (s, 3H, CH3), 3.67 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 3.99 (t, 2H, CH2), 4.27 (bs, 2H, CH2), 5.31 (s, 2H, CH2), 7.66 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.17 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 505 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:11]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]2=[O:24])=[CH:20][CH:19]=1
Reactant: O=c1n(CCCC2CCCCC2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2ccn(CCCC3CCCCC3)c2=O)cc1
Temperature: 70 °C

Procedure:
1-(3-Cyclohexyl-propyl)-3-(4-nitro-phenyl)-1,3-dihydro-imidazol-2-one (15.4 g, 46.8 mmol) and tin chloride dihydrate (53.0 g, 234.5 mmol, 5.0 equiv) were combined in ethanol and heated at 70° C. for two hours. The mixture was cooled to 25° C. and poured onto ice (500 mL). The aqueous mixture was adjusted to pH=8 with 1 N aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated in vacuo to an orange solid (13.4 g, 95%). Mp 83-85° C.; 1H NMR (CDCl3, 300 MHz) δ 7.26 (d, 8.5 Hz, 2 H), 6.64 (d, 8.5 Hz, 2 H), 6.40 (d, 2.9 Hz, 1 H), 6.24 (d, 2.9 Hz, 1 H), 3.70 (br s, 2 H), 3.57 (t, 7.4 Hz, 2 H), 1.64 (m, 7 H), 1.19 (m, 6 H), 0.85 (m, 2 H); MS (CI) m/z 300 (MH+); Rf =0.24 (50:50 hexane/ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1)=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](=[O:35])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[C:21]2[O:22][CH:23]=[CH:24][N:25]=2)=[CH:32][N:31]=1)=[O:29]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COC(=O)c1ccc(C(=O)NCc2c(-c3ncco3)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
5-[(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyridine-2-carboxylic acid methyl ester was prepared starting from intermediate A and 6-(methoxycarbonyl)nicotinic acid. MS calcd. for C27H20ClN4O5 [(M+H)+] 515.1, obsd. 515.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][O:12]2)(=O)=O.CCCC[Sn]([C:47]1[CH:52]=[CH:51][CH:50]=[N:49][CH:48]=1)(CCCC)CCCC.O>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:18]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]1[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[O:12][CH2:11]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cccnc4)c3C2)cc1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Palladium-tetrakis(triphenylphosphine) (48 mg, 0.042 mmol) and (3S)-3-(dibenzylamino) -3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (200 mg, 0.42 mmol) in dioxane (4 mL) were added to 3-(tri-N-butylstannyl)pyridine (232 mg, 0.63 mmol) under an atmosphere of argon and the resulting reaction mixture was irradiated in a microwave at 120-140° C. for 1.5 h. More palladium-tetrakis(triphenylphosphine) (48 mg, 0.042 mmol) was added and the irradiation was continued at 140° C. for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic phases was dried over sodium sulfate, the solvent was evaporated in vacuo and the residue purified by column chromatography, using a gradient of ethyl acetate in heptanes as the eluent, gave 63 mg (74%) of the title compound: MS (ES) m/z 407[M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:16]=1.[CH3:17]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:17])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]([CH3:14])[CH3:15])[C:6]=2[N:16]=1
Reactant: CC(=O)N(C)C
Reactant: CC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.096 g (0.0004 mole) of 2-chloro-9-isopropyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-43), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.088 g of 2-chloro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-43) as an yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Temperature: 120 °C

Procedure:
5-Chloro-6-(quinolin-3-yloxy)-pyridin-3-yl amine (1 mmol) (obtained as per procedure described in preparation 1) was dissolved in toluene under heating. To the clear solution was added succinic anhydride (1 mmol) and refluxed at 120° C. for 6 hours. The solvent the evaporated and the crude obtained was purified by column chromatography to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)n[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1n[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
A solution of 6-methoxy-3-methyl-1 H-indazole(2.0 g, Reference Example 49) in dichloromethane (75 ml) was cooled to 0° C. then treated with a solution of boron tribromide in dichloromethane (54 ml, 1M). The mixture was allowed to warm to room temperature and then stirred for 12 hours. The solution was poured into an ice-saturated sodium bicarbonate mixture and the aqueous layer was extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (2:1, v/v) to yield the title compound (1.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 95 %

Procedure:
Chiral hydrogenation of acetophenone was carried out (see formula (7) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using acetophenone (150 mg; 1.25 mmol) as the substrate and 2-propanol (1.5 mL) as the solvent. However, the hydrogen pressure was set to 1 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 12 hours. As a result, (R)-1-phenylethanol was obtained at a conversion rate of 99%, isolation yield of 95% (293 mg; 1.19 mmol), and enantiomeric excess of 97%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[CH:5]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)=O>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH2:12])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: C=C(c1ccccc1)c1cc(C(=O)OC)ccc1O
Solvent: CC(C)=O
Product: C=C(c1ccccc1)c1cc(C(=O)OC)ccc1OCc1ccccc1
Yield: 79.7 %

Procedure:
To a solution of 1.50 g (5.9 mmole) 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid methylester and 1.04 g (6.1 mmole) benzyl bromide in 10 ml abs. acetone 1.24 g (8.9 mmole) potassium carbonate are added. The reaction mixture is then heated for 4 hours with recycling. Following cooling of the suspension, it is filtered and the residue is washed with 50 ml diethtylether. The solvent is removed and the raw product obtained is cleaned by column chromatography (silica gel, petroleum ether/MTBE=5/1 (v/v)). 1.62 g (4.7 mmole, 80%) 4-benzyloxy-3-(1-phenyl-vinyl)-benzoic acid-methylester are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.Cl.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2cc(Cl)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1ccc2cc(Cl)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-chloro-2-naphthyl)carbamic acid ethyl ester (725 mg, 2.90 mmol), N-chlorosuccinimide (387 mg, 2.90 mmol) and 1 M HCl in acetic acid (2.90 mL, 2.90 mmol) in acetic acid (20 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature, water (10 mL) is added and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator to give N-(1,6-dichloro-2-naphthyl)carbamic acid ethyl ester as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:16])[CH2:14][CH3:15].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(Br)cncc21
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a stirred black solution of (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (317 mg, 1.4 mmol) and propionic acid (115 μL, 1.54 mmol) in CH2Cl2 (7.0 mL) at 0° C. was added EDCI (295 mg, 1.54 mmol), stirring was continued over night and the reaction mixture was allowed to warm up to RT. The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution. The combined organic phases were dried over Na2SO4, filtered, evaporated and purified by precipitation CH2Cl2/n-pentane to afford the title compound (365 mg, 92%) as light brown solid. MS: 283.0 (M+H+, 1 Br).
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11]O)[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:18].O>C(OCC)C>[Br:18][CH2:11][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 9.2 g (35.7 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 10.0 g (yield: 87.3%) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole.