Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:3]2[CH2:4][CH2:5][S:1][CH:2]2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1NCCS1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1SCCN1C(=O)c1ccc(F)cc1

Procedure:
The solution of ethyl thiazolidine-2-carboxylate (24.18 g, 0.15 mol) in abs. CH2Cl2 (80 ml) is treated dropwise at RT with the solution of 4-fluorobenzoyl chloride (23.78, 0.15 mol) in abs. CH2Cl2 (20 ml). The solution warms to 38° C., the solvent begins to boil and HCl is released. It is kept under reflux for 4 h with heating.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[O:18][CH3:19]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:18][CH3:19])[C:11]([Br:10])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1cc(N)ccc1Br
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1Br

Procedure:
(2-amino-5-bromo-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xd) was prepared by reacting 2-chlorobenzaldehyde with 0.086 moles of 4-bromo-3-methoxy aniline in a manner analogous to Example 1. MH+/Z=340.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=1.O.[O-:17][C:18]#[N:19].[K+].C(O)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]([NH2:19])=[O:17])=[N:6][CH:7]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)CNCc1ccc(Br)cn1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(Br)cn1)C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Ethyl 2-((5-bromopyridin-2-yl)methylamino)acetate (9J1) (41.6 mmol, 11.37 g) was dissolved in dioxane (80 ml) and water (80 ml) and potassium cyanate (62.4 mmol, 5.07 g) added. After 10 min, acetic acid (133 mmol, 8.00 g) was added and the reaction mixture stirred at room temperature under nitrogen overnight. The reaction mixture was quenched with saturated sodium bicarbonate (to pH 8-9) and then extracted with dichloromethane (3×). The organic layers were combined, washed with water, brine and dried using a hydrophobic frit, then concentrated under reduced pressure to give ethyl 2-(1-((5-bromopyridin-2-yl)methyl)ureido)acetate (9J2) 11.08 g (84%) which was used without further purification. 1H NMR (400 MHz, CDCl3) 8.61 (d, 1H) 7.84 (dd 1H) 7.39 (d, 1H) 5.35 (bs, 2H) 4.51 (s, 2H) 4.17 (q, 2H) 4.11 (s, 2H) 1.25 (t, 3H)
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)ccc1O
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A solution of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (111 g, 0.248 mol) in methylene chloride is cooled to -5° C., treated over one hour with a 1 M solution of boron tribromide in methylene chloride (322 mL, 0.322 mol), stirred for one hour, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid (105 g, 98.1%) which is identified by NMR spectral analyses.
Reaction SMILES: [C]=O.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1.[CH:37]([O-])=[O:38].[Na+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH:37]=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(Br)ccc23)cc1
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C=O)ccc23)cc1
Yield: 82.6 %

Procedure:
Carbon monoxide was bubbled through a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 55, 400 mg, 0.79 mmol), sodium formate (107 mg, 1.57 mmol) and dichlorobis(triphenylphosphine)-palladium (II) (11 mg, 0.016 mmol) in dimethylformamide (6 ml) at 110° C. for 4 h. The reaction mixture was cooled and extracted from 1N hydrochloric acid with ethyl acetate (2×50 ml). The organic layers were dried (MgSO4) and concentrated. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (320 mg) as a fawn solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[CH2:21]([Zn+])[CH2:22][CH2:23][CH3:24]>C1COCC1.CCOC(C)=O.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>[CH2:21]([C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Zn+]
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (300 mg, 0.822 mmol) and tetrakis(triphenylphosphine)palladium(0) (950 mg, 0.822 mmol) in THF (4 ml) was added n-butyl zinc bromide (0.5 M solution in THF) (1.644 ml, 0.822 mmol) and the reaction mixture was heated at 60° C. for one hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give ({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (210 mg, 0.614 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 (s, 2H), 6.97 (s, 1H), 6.68 (s, 1H), 6.64 (s, 1H), 3.71 (s, 2H), 2.50 (t, 2H), 1.88 (br. s., 2H), 1.45 (quin, 2H), 1.14-1.29 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[CH3:35][O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:32]=[CH:33][CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][CH:47]([N:50]5[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]5)[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH3:35])[N:7]=2)[CH:19]=1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 175 °C
Yield: 64.7 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 194, step B) (80 mg, 0.17 mmol) and 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, step B) (61 mg, 0.17 mmol) in 2,2,2-trifluoroethanol (0.80 mL) was added 4 M HCl in dioxane (84 μL, 0.33 mmol). The mixture was stirred and heated on a microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (95 mg, 0.11 mmol, 70%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.47 (br s, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 8.20 (d, 1H, J=5.13 Hz), 8.06 (d, 1H, J=7.87 Hz), 7.82 (d, 1H, J=7.69 Hz), 7.59-7.64 (m, 2H), 7.34-7.45 (m, 2H), 7.21 (t, 2H, J=8.15 Hz), 7.02-7.08 (m, 1H), 6.68-6.71 (m, 1H), 6.50 (dd, 1H, J=2.11, 8.70 Hz), 6.45 (d, 1H, J=5.13 Hz), 3.73-3.81 (m, 5H), 3.06-3.11 (m, 4H), 2.85 (s, 3H), 2.68 (t, 2H, J=11.45 Hz), 2.58-2.62 (m, 4H), 2.38-2.46 (m, 1H), 1.80-1.87 (m, 2H), 1.48-1.60 (m, 2H). MS (ESI): 812 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:26]C)=[C:21]([CH:25]=3)[C:22]([OH:24])=[O:23])[N:15]=2)[NH:10][C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([OH:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=[O:23])[N:15]=2)[NH:10][C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a suspension of 5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-methoxybenzoic acid (105.9 mg, 0.282 mmol) in DCM (10 mL) at −78° C. was added BBr3 (1 M in DCM, 0.563 mL, 0.563 mmol) in a dropwise fashion. The mixture was allowed to warm to room temperature and stirred vigorously for 16 hours. After concentration under reduced pressure, the residue thus obtained was purified by column chromatography [silica gel; MeOH/DCM (1:9)] to give the product as a brown powder (82 mg, 80%). 1H NMR (400 MHz, DMSO): δ 12.02 (s, 1H), 8.34-8.33 (m, 2H), 7.87 (dd, J=3.0, 11.6 Hz, 1H), 7.41-7.27 (m, 5H), 6.77 (d, J=12.0 Hz, 1H), 5.07 (s, 2H). MS: 363.1 (M+H).
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH3:7][C:8]([CH3:16])([CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:9]#N>C1(C)C=CC=CC=1>[C:14]([CH:13]1[C:7](=[O:4])[C:8]([CH3:16])([CH3:9])[CH2:11][CH2:12]1)#[N:15]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C#N)CCCC#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C#N)C1=O
Reaction time: 2 h
Yield: 55 %

Procedure:
A suspension of potassium t-butoxide (60.2 g, 0.54 mole) in toluene is treated with 2,2-dimethyladiponitrile (120.7 g, 0.87 mole) at 80° C., stirred for 2 hours, cooled to less than 30° C., and quenched with water. The phases are separated, the organic phase is stirred with 3N hydrochloric acid and filtered. The filtrate is concentrated in vacuo to give an oil which is distilled (2 torr, 150° C.) twice to afford the title product as a colorless oil, 65.7 g (98.5% pure, 55% yield), identified by gas chromatography.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 150 °C
Yield: 58 %

Procedure:
To a 250 mL pressure bottle equipped with magnetic stirring was added methyl 2-fluorobenzoate (Lancaster Synthesis Inc.) (3.0 g, 20 mmol), 1-benzylpiperazine (Aldrich) (3.8 g, 22 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (100 mL) The mixture was heated at 150° C. for 12 h. After cooling to RT the reaction was diluted with EtOAc (100 mL) and H2O was added. The organic layer was separated and washed with H2O, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a brown oil. The crude material was purified by column chromatography (4:1 hexanes-EtOAc) to give the title compound as a white foam (3.6 g). MS (ESI, pos. ion) m/z: 311 (M+H). Calc'd for C19H22N2O2: 310.17.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Yield: 251.5 %

Procedure:
Title compound 38 (1.70 g, 1.98 mmol), Pd (C) 10% (0.17 g, 10% w/w) and MeOH were put in a Parr-Shaker apparatus and the reaction mixture was pressurized to 55 PSI of H2. The mixture was agitated over night. The catalyst was filtered and the filtrate was concentrated to afford title compound 39 (1.55 g, 100%) as a clear oil. LRMS (ESI): (calc) 311.08 (found) 312.1 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18]O>Cl>[CH3:18][O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([OH:13])=[C:7]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Reactant: CO
Agent: Cl
Product: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 4-hydroxymethyl-2,6-di-t-butylphenol (0.5 g) in methanol (10 mL) containing 1 drop of concentrated hydrochloric acid was stirred at ambient temperature for 1 hour. Evaporation of the solvent gave the title compound, 0.5 g, 94% yield as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([OH:14])[N:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CN(C)C=O.Cl>[C:22]([O:25][CH2:26][CH2:27][O:14][C:5]1[N:4]([CH3:15])[N:3]=[C:2]([NH2:1])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=[O:24])[CH3:23]
Reactant: Cc1ccc(-c2c(N)nn(C)c2O)cc1
Reactant: CC(=O)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1c(-c2ccc(C)cc2)c(N)nn1C
Reaction time: 0.75 h
Yield: 12.7 %

Procedure:
To 3-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-ol (Preparation 3b) (855 mg) in dimethylformamide (10 ml) at room temperature was added cesium carbonate (4.11 g) and 2-bromoethyl acetate (703 mg), the mixture was stirred for 45 minutes. The reaction was diluted with 2M hydrochloric acid (10 ml) and extracted with ether (2×100 ml). The organic fractions were combined, washed with water (2×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with ethyl acetate:hexane (5:1) to yield the title compound as a white solid (155 mg).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][N:20]4C(=O)C5=CC=CC=C5C4=O)[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.NN.O>CO>[C:1]1([CH3:31])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(CN4C(=O)c5ccccc5C4=O)cc3C2)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(CN)cc3C2)cc1
Yield: 99.3 %

Procedure:
21.6 g of 2-(p-toluenesulfonyl)-5-phthalimidomethylisoindoline and 5 ml of hydrazine hydrate was dissolved in 300 ml of methanol and the solution was heated under reflux for 2 hours. After reaction mixture was allowed to cool, 50 ml of water was added to it. The mixture was concentrated to a half volume under reduced pressure. To the residue 500 ml of 10% aqueous sodium hydroxide and 1 liter of chloroform were added and the whole mixture was thoroughly shaken. The chloroform layer was separated and washed with 5% aqueous sodium hydroxide and then with water. After removing the solvent by evaporation, the residue was recrystallized from ether to give 15.0 g of 2-(p-toluenesulfonyl)-5-aminomethylisoindoline.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: NC(CO)CO
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NC(CO)CO)nc21
Yield: 95.9 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.5 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.33 g (3.64 mmol) of serinol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.51 g (96%) of the title compound: mp 168° C.–172° C. MS (APCI) (m+1)/z 440.1
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[NH:21][CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:30]([CH:32]=O)=[O:31].O.[BH3-]C#N.[Na+]>CO.CC#N.O.C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[N:21]([CH2:32][CH2:30][OH:31])[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1
Reactant: O=CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1CCO
Reaction time: 0.33 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropanecarboxamide (340 mg, 0.86 mmol) in anhydrous MeOH (5.7 mL) containing 1% of acetic acid was added glyoxal 40% in water (0.60 mL, 5.2 mmol) at room temperature under N2. After 20 min of stirring, NaBH3CN (120 mg, 1.9 mmol) was added in one portion and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue obtained was purified by column chromatography on silica gel (10-40% ethyl acetate/hexanes) providing a pale yellow oil which was treated with 50/50 CH3CN—H2O containing 0.05% TFA and CDCl3. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (20-35% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-(2-hydroxyethyl)-1H-indol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=7.7 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 6.93 (dd, J=1.6, 7.9 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.08 (s, 1H), 5.92 (s, 2H), 4.21 (dd, J=6.9, 6.9 Hz, 2H), 3.68 (m, 2H), 2.28 (s, 1H), 1.60 (dd, J=3.7, 6.7 Hz, 2H), 1.35-1.32 (m, 9H), 1.04 (dd, J=3.7, 6.8 Hz, 2H). MS (ESI) m/e (M+H+) 439.0.
Reaction SMILES: [CH:1]([N:4]([CH:11]([CH3:13])[CH3:12])[C:5](=[O:10])[C:6]([O:8]C)=[O:7])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:11]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:10])[C:6]([OH:8])=[O:7])([CH3:13])[CH3:12]
Reactant: COC(=O)C(=O)N(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C(=O)C(=O)O)C(C)C
Yield: 35.4 %

Procedure:
550 mg of methyl N,N-di-isopropyloxamate was dissolved in 20 ml of methanol. The resulting solution was stirred under ice-cooling, to which 15 ml of 1N aqueous solution of sodium hydroxide was added dropwise. After completion of the dropwise addition, the resultant mixture was stirred for 1 hour at room temperature. The solvent was distilled off from the resulting reaction solution under reduced pressure. The residue was added with 20 ml of 1N HCl. Insoluble white precipitates were collected by filtration, washed with chilled water and n-hexane, and then dried to obtain 180 mg of the title compound, N,N-di-isopropyloxamic acid as white solids.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=S)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(#N)C.[Hg]Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCCN
Reactant: CCCCc1ccc(N=C=S)cc1
Agent: Cl[Hg]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1ccc(N=C2NCCCN2)cc1
Reaction time: 1 h

Procedure:
A solution of 144 g. of 4-n-butylphenylisothiocyanate in 800 ml of acetonitrile is added dropwise in 30 minutes at room temperature to a solution of 95 ml of 1,3-diaminopropane in 450 ml of acetonitrile, while solution is stirred. After 1 hour, 260 ml of triethylamine are added. A solution of 212 g of mercurychloride in 560 ml of acetonitrile is then added while stirring said solution for 1 hour. The reaction mixture is stirred for another 24 hours and then filtered while warm. The solvent is distilled from the filtrate and the residue is mixed with up in methylene chloride and washed with dilute alkaline solution and water. After drying, the methylene chloride is distilled off, the crude 2-(4-n-butylphenyl)iminohexahydropyrimidine being obtained in a yield of 165 g. The product can be purified by a recrystallisation from a mixture of carbon tetrachloride and petroleum ether. A product is obtained with a melting point of 116°-119° C. The product may also be purified by dissolving it in approximately 20% hydrochloric acid, washing the aqueous phase with ether and then making it alkaline again. The thus purified 2-(4-n-butylphenyl)imino-hexahydropyrimidine can be isolated by taking up in ether, drying and distilling the solvent. The thus purified product also has a melting point of 116°-119° C.