Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>CN(C)C=O>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[CH2:16][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a slurry of NaH (0.29 g, 12.25 mmol) in 25 mL dimethylformamide under nitrogen at 0° C. is added portionwise 7-hydroxy-1-tetralone (2.0 g, 12.33 mmol) over 5 minutes. After half an hour, 2-(chloromethyl)quinoline (2.2 g, 12.43 mmol) is added in 10 mL dimethylformamide. The ice bath is removed and the reaction mixture is stirred overnight. The solvent is then removed in vacuo and the residue is partitioned between 1N sodium hydroxide and methylene chloride. The organic layer is separated, dried over magnesium sulfate, evaporated down to an oil, and chromatographed on silica gel. Elution with 9-1 methylene chloride/ethyl acetate gives 2.0 g(54%). This material is recrystallized from acetonitrile to afford 1.3 g (35%) of yellow crystals, m.p. 98.5°-101.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)=[O:8].O1CCCC1.[OH-].[Li+].Cl>O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)=[O:8]
Reactant: CCOC(=O)c1ccc2c(cnn2CCC(=O)Nc2ncc[nH]2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCn1ncc2cc(C(=O)O)ccc21)Nc1ncc[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 37 %

Procedure:
A mixture of the product of Example 1327b Part C (145 mg, 443 μmol), tetrahydrofuran (2 mL) and water (2 mL) was treated with aqueous lithium hydroxide (1.0 M; 0.56 mL, 560 μmol) and stirred at room temperature for 21 h. The reaction was incomplete by thin-layer chromatography, so additional lithium hydroxide solution (a total of 1.35 mL) was added in four portions over the next 8 h. After stirring for 16 h more, the reaction was acidified with aqueous hydrochloric acid (1.0M) and concentrated under vacuum. The residue was partitioned between water and dichloromethane, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to provide the title product (49 mg, 37%): 1H NMR (DMSO-d6) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 6.67 (s, 2H), 4.73 (t, 2H), 3.00 (t, 2H); High resolution mass spectrum (NH3 --CI) calculated (M+H+) 300.1097, found 300.1097.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CO)o1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CCl)o1

Procedure:
2-(5-Hydroxymethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)- dione (10 g) was dissolved in thionyl chloride (15 ml) with the aid of gentle heat. The solution was evaporated to dryness and the solid residue re-evaporated with cyclohexanebenzene (1:1). The residue was suspended in ether, the suspension filtered, washed with ether and dried to give 2-(5-chloromethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)- dione (10.1 g) m.p. 119°-122° (dec.). Analysis Found: C, 61.32; H, 3.71; N, 5.00. C14H10ClNO4 requires: C, 60.99; H, 3.66; N, 5.08%.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11](=[O:13])[CH3:12])[N:7]=1>C1COCC1>[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])[N:7]=1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1noc(C)n1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1noc(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a solution of ethynylmagnesium bromide (0.5 M in THF, 800 mL, 400 mmol) at 0° C. was added 1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanone (33.5 g, 266 mmol) in THF (533 mL) slowly. The reaction was allowed to warm to room temperature and stirred for 5 hours. After being quenched with saturated NH4Cl (750 mL) at 0° C., the THF was removed in vacuo and the aqueous residue was extracted with ethyl acetate (600 mL×2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give dark brown oil. The dark brown oil was purified by silica gel column chromatography use 10% of ethyl acetate in hexanes as eluent to give the title compound (36 g, 89%), 1H NMR (CDCl3, 400 MHz): delta 3.93 (s, 1H), 2.63 (s, 1H), 2.61 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([C:25](O)=O)=[N:10]1.[CH3:28][C:29]([NH:34][CH3:35])([CH3:33])[C:30]([NH2:32])=[O:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([C:25]2[N:34]([CH3:35])[C:29]([CH3:33])([CH3:28])[C:30](=[O:31])[N:32]=2)=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Reactant: CNC(C)(C)C(N)=O
Product: Cc1c(C2=NC(=O)C(C)(C)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1

Procedure:
Compound 20 was synthesized from 4h (251 mg, 0.60 mmol) and 5a (130 mg, 1.08 mmol) as a white solid (176 mg, 60%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 2H), 7.46 (d, 1H), 7.28 (m, 3H), 7.22 (d, 1H), 3.49 (s, 3H), 2.42 (s, 3H), 1.42 (s, 6H); ESMS m/z: 495.1 (M+1).
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1.O>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][CH:4]2[NH2:1]
Reactant: Cc1cccc2c1CCC2N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1CCC2N
Temperature: 25 °C

Procedure:
1.0 g (5.8 mmol) 1-azido-4-methyl-indane is treated with 4.54 g (17.3 mmol) triphenylphosphine in 26 ml THF and 1.4 ml H2O at room temperature overnight. Completion of the reaction is achieved by heating up the mixture for additional 2.5 hours. The reaction mixture is then cooled to room temperature and diluted with water. The pH is adjusted to 2 by adding cold (ca 0° C.) aqueous HCl (1M). After extraction with EtOAc the aqueous layer is separated, basified with NaOH (2M) and extracted into EtOAc. The organic layer is then dried (MgSO4) and concentrated in vacuo to give 4-methyl-indan-1-yl-amine as a light yellow liquid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[O:11]=[C:12]1[C:17]2[S:18][CH:19]=[C:20]([S:21](Cl)(=[O:23])=[O:22])[C:16]=2[CH2:15][CH2:14][CH2:13]1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[S:21]([C:20]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:11])[C:17]=2[S:18][CH:19]=1)(=[O:22])=[O:23]
Reactant: CNCCc1cccnc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: CN(CCc1cccnc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From methyl-(2-pyridine-3-yl-ethyl)-amine (the compound of Preparation Example 15) (82 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo-[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (150 mg), the title compound (138 mg) was obtained as a colorless oily matter, in the same way as Preparation Example 41.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]5[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:47][CH:46]=5)[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)c3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and 4-(methylsulfonyl)benzoic acid (56.7 mg, 0.283 mmol) using a similar method to that employed for Example 14 (3%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:29]1[CH2:30][CH2:31][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:28]1)(=[O:34])[CH3:33]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:10]2[O:9][C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2oc(SC)nc12
Reactant: C1CCNCC1
Product: COc1ccc(Br)c2oc(N3CCCCC3)nc12

Procedure:
Starting from 7-bromo-4-methoxy-2-methylsulfanylbenzooxazole (10.0 g) and piperidine (3.8 ml). Purification by chromatography on silica eluting with 30-100% ethyl acetate in hexane afforded the title compound as an off-white solid (10.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Yield: 83.2 %

Procedure:
A solution of methyl 2-hydroxy-4-[2-(phenethyl)phenethyl]benzoate (0.25 g) in THF (5 ml) and methanol (5 ml) containing aqueous 2N sodium hydroxide (5 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to small volume and acidified with aqueous 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate (25 ml each time) and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. The solid obtained on removal of the solvent was crystallised from a mixture of diethyl ether and hexane to give 2-hydroxy-4-[(2-phenethyl)phenethyl]benzoic acid (0.2 g), m.p. 134°-7° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2N=C(C)S[C:6]=2[N:7]=1.[CH3:13][C:14]1[S:15]C2C(=O)NC(=O)NC=2[N:24]=1>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[S:15][C:14]([CH3:13])=[N:24][C:6]=2[N:7]=1
Reactant: Cc1nc2c(Cl)nc(Cl)nc2s1
Reactant: Cc1nc2[nH]c(=O)[nH]c(=O)c2s1
Product: Cc1nc2nc(Cl)nc(Cl)c2s1

Procedure:
Prepared using the method used in the preparation of 5,7-dichloro-2-methyl-thiazolo[5,4-d]pyrimidine using 2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione in place of 2-methyl-4H-thiazolo[5,4d]pyrimidine-5,7-dione. The title compound was obtained as an solid solid (140 mg, 28%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[N:20][C:13]=3[N:12]=[C:11]2[C@H:21]([N:23]([CH2:38][CH2:39][C:40](=O)[CH3:41])[C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH3:22])=[CH:6][CH:5]=1)[CH3:2].[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH:43]1([NH:47][CH:40]([CH3:41])[CH2:39][CH2:38][N:23]([C@@H:21]([C:11]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[N:20][C:13]=3[N:12]=2)[CH3:22])[C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:35])([F:36])[F:34])[CH:27]=2)[CH2:46][CH2:45][CH2:44]1
Reactant: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)=O)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)NC3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1

Procedure:
E3 (67 mg, 0.11 mmol), cyclobutyl amine (14.7 μL, 0.17 mmol), and sodium triacetoxyborohydride (73 mg, 0.34 mmol) were stirred in dichloroethane at room temperature for 3 h. The reaction mixture was diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, concentrated in vacuo. Purified by chromatography (4% to 10% methanol with 0.1% ammonium hydroxide in dichloromethane), recovering 31 mg of E4.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:42])(=O)=O)=CC=1>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:42])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g, 2.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (1.2 mL, 3.0 mmol, 2.5M) at -78° C. After 20 minutes, N-fluorobenzenesulfonimide (0-8 g, 3.2 mmol) is added to the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and IN hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:21]3[C:20](=[O:22])[NH:19][CH:18](O)[C:17](C)([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[C:27]([O-])(O)=O.[Na+]>OS(O)(=O)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:27])=[C:17]([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: O=C([O-])O
Reactant: CC1(C)c2ccc3nc(Nc4c(Cl)cccc4Cl)[nH]c3c2C(=O)NC1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)[nH]c32)c1C
Yield: 84 %

Procedure:
2-(2,6-Dichlorophenylamino)-6,6-dimethyl-7-hydroxy-7,8-dihydro-1H,6H-imidazo[4,5-h]isoquinoline-9-one (from Example 2) (45 mg, 0.11 mmol) was suspended in conc. H2SO4 (10 mL) and the resultant mixture was stirred at ambient temperature for 15 min. The solution was poured over ice, neutralized with NaHCO3 and filtered. The filtrate was triturated with water (10 mL) and centrifuged. The liquid was decanted, and the residual solid was triturated with methanol and centrifuged. The supernatant was decanted and the residue dried to give the title compound (35 mg, 84%). Mp>300° C.; MS (ES) 373 (MH+).
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([N:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:20]([C:22]1[N:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)N.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:20]2[C:4](=[O:19])[C:5]([N:10]3[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]=[CH:11]3)=[CH:6][NH:7]2)=[N:27][CH:26]=1
Reactant: NNc1ccc(CO)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1c(-n2cnc(C(F)(F)F)c2)c[nH]n1-c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (3.6 mmol) of the compound from Example 44A and 502 mg (3.6 mmol) of the compound from Example 4A are dissolved in 1 ml glacial acetic acid and the mixture is stirred at RT for 16 h. Thereafter, 200 mg (1.4 mmol) of the compound from Example 4A are again added and the mixture is stirred at RT for a further 20 h. The reaction mixture is taken up in 5 ml ethyl acetate and the mixture is adjusted to pH 7 with dilute aqueous sodium bicarbonate solution. The aqueous phase is concentrated in vacuo, 1.5 ml (4.0 mmol) 21% strength ethanolic sodium ethylate solution are added to the residue and the mixture is stirred at RT for 4 h. The precipitate is filtered off and washed with ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15]O.O.[BrH:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15][Br:18]
Reactant: OCc1c(Cl)cccc1Oc1ccccc1
Reactant: Br
Solvent: O
Product: Clc1cccc(Oc2ccccc2)c1CBr

Procedure:
17.5 g (70.94 mmol) of (2-chloro-6-phenoxy-phenyl)-methanol are heated under reflux for 3 hours in 150 ml of 48% hydrobromic acid. The mixture is cooled, water is added and the mixture is extracted 3× with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 21.21 g (>1 00%) of crude (2-chloro-6-phenoxy-phenyl)-bromomethane are obtained in the form of a yellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.70; 1H-NMR (CDCl3, 200 MHz): 4.78 (s, 2H); 6.70-7.41 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:8]=[C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Reactant: OB(O)c1cccc(Cl)c1
Product: Nc1ccc(CC2CCCC2)cc1-c1cccc(Cl)c1

Procedure:
2-bromo-4-cyclopentylmethylaniline and 3-chlorobenzene boronic acid can be combined to form 2-(3-chlorophenyl)-4-cyclopentylmethylaniline,
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([S:7][CH3:8])=[CH:3][CH:2]=1.[Cl:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Cl:10][CH2:8][S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1ccc(C)cc1
Solvent: Clc1ccccc1
Product: Cc1ccc(SCCl)cc1
Yield: 109.7 %

Procedure:
Methyl p-tolyl sulfide (75 g, 542.27 mmol) was diluted in chorobenzene (452 mL). N-Chloro Succinimide (NCS) (76.07 g, 1.05 eq) was added in small portions maintaining the temperature between 35° C. and 45° C., under an argon atmosphere. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, a solid separated out from the solution. The suspension was filtered, and the solid washed with chlorobenzene (50 ml). The filtrate was washed with water (3×225 mL). The resulting organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by distillation to give 102.68 g (100%) of the desired product as yellow oil (bp: 96° C. at 40 Pa).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9]>C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:9][C:8](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: NC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCCC(NC(=O)OCc2ccccc2)C1
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a solution of 2-cyclohexen-1-one (1.442 g, 15.0 mmol) in anhydrous methylene chloride (15 mL) was added bis(acetonitrile)dichloro-palladium(II) (0.231 g, 1.0 mmol) and benzyl carbamate (1.497 g, 9.9 mmol) and stirred under nitrogen for 24 hrs. The reaction mixture was filtered through a pad of silica gel, washing with ethyl acetate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-65% ethyl acetate/hexanes) to give a pale yellow low melting solid (1.9 g). 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.09 (s, 2H), 4.81 (br s, 1H), 3.99 (br s, 1H), 2.73 (m, 1H), 2.36-2.26 (m, 3H), 2.11-1.97 (m, 2H), 1.67-1.64 (m, 2H). ESI m/z: 248.0 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([NH2:20])[N:10]=1.[C:21]([O:25][C:26]([NH:28][C:29](N1C=CC=N1)=[N:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].O>C(Cl)Cl>[NH2:20][C:11]1[N:10]=[C:9]([NH:8][C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH:1][C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=1
Reactant: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3N)c2c1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of 4.53 g of N4-[(1S,2R)-2-aminocyclohexyl]-6-methylquinazoline-2,4-diamine in 90 ml of methylene chloride, 5.18 g of N,N′-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine was added, and then the mixture was stirred at room temperature for 15 hours. The reaction solution was mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 8.50 g of the desirable compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([Cl:16])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([OH:28])[CH:22]=[N:23][C:24]=1[CH:25]1[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:16][C:15]1[C:3]([CH2:2][O:28][C:21]2[CH:22]=[N:23][C:24]([CH:25]3[CH2:27][CH2:26]3)=[C:19]([Cl:18])[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
To a stirred solution of tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (Preparation 25, 2.50 g, 7.99 mmol) and 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 42 WO2012007869, 1.13 g, 6.66 mmol) in DMSO (25 mL) was added K2CO3 (2.76 g, 19.9 mmol). The resulting mixture was stirred under nitrogen at room temperature for 18 hours. The reaction mixture was then quenched with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (30 mL), dried over MgSO4 and evaporated under reduced pressure to give the crude product (2.69 g). Purification was accomplished by column chromatography on silica (eluting with 1:9 Et2O/cyclohexane) affording the title compound (1.24 g, 46%).