Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:20]=[CH:19][C:15]3[CH:16]=[N:17][S:18][C:14]=3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=2[F:30])=[O:11])[CH2:4][O:3]1.Cl>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[CH:16]=[N:17][S:18][C:14]=2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=1[F:30])=[O:11]
Reactant: CSc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)ccc3cnsc23)c(F)c1
Agent: Cl
Solvent: CO
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)ccc3cnsc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of 7-(2-fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazole-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (170 mg, 0.37 mmol) in MeOH (2 mL) was added a 1.0M aqueous solution of hydrochloric acid (0.80 mL). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, MeOH in DCM) to afford the title compound as a yellow solid (42 mg, 26%). LCMS (Method A): RT=8.80 min, [M+H]+=478. 1H NMR (CD3OD) 8.81 (1 H, s), 7.63-7.56 (2 H, m), 7.12-7.04 (3 H, m), 4.10-4.04 (1 H, m), 3.98-3.86 (2 H, m), 3.64-3.55 (2 H, m), 2.50 (3 H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH2:15])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1
Reactant: COC(=O)C(CN1CCc2[nH]ncc2C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)CN1CCc2[nH]ncc2C1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-3-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.55 g, 1 equiv.) in methylene chloride (5 mL, 0° C.) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and passed onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2 M ammonia in methanol to afford the product as its free base (275 mg, 95%). 1H-NMR (CDCl3, 500 MHz) δ 2.71 (dd, J=12.8, 8.6, 1H), 2.74-2.91 (m, 6H), 3.48 (s, 2H), 3.54 (d, J=13.4, 1H), 3.62 (d, J=13.4, 1H), 3.69 (dd, J=8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spec.: 225.16 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[O:5][CH2:4][CH2:3]1.[OH-].[NH4+:10].CCO>O1CCCC1>[NH2:10][CH2:4][CH2:3][CH:2]([S:6]([OH:5])(=[O:8])=[O:7])[CH3:1]
Reactant: CC1CCOS1(=O)=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CCN)S(=O)(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 2,4-butanesultone (1.0 g, 7 mmol) in tetrahydrofuran (THF, 4.0 mL) was added via syringe pump over a 4 h period to ammonium hydroxide (28-30% NH3, 43 mL, 350 mmol) at 5° C. The solution was stirred at 5° C. for an additional 30 minutes. The solvent was coevaporated with EtOH (3×25 mL). The solid was dried in vacuo. Yield: 94%. 1H NMR (D2O, 500 MHz) δ ppm 3.05 (m, 2H), 2.90 (m, 1H), 2.05 (m, 1H), 2.06 (m, 1H), 1.77 (m, 1H), 1.18 (d, 3H, J=6.8 Hz), 1.14 (t, 3H, J=7.3 Hz). 13C (DMSO, 125 MHz) δ ppm 52.75, 38.20, 30.87, 17.27. ES-MS 154 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1Br.[Cu][C:21]#[N:22].C([O-])(O)=O.[Na+].CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1[C:21]#[N:22]
Reactant: N#C[Cu]
Reactant: CSc1ncc2c(N)c(Br)c(=O)n(C3CCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1ncc2c(N)c(C#N)c(=O)n(C3CCC3)c2n1
Temperature: 220 °C
Yield: 67.3 %

Procedure:
To a solution of 5-amino-6-bromo-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.15 mmol) in 0.5 mL NMP was added copper(I) cyanide (56 mg, 0.63 mmol). The resulting mixture was heated at 220° C. in a microwave reactor for 20 min. After cooling, the reaction mixture was treated with a mixture of NaHCO3 (sat'd, aq) and EtOAc. The mixture was filtered and the collected solid then mixed with NH4OH (15%, aq). The aqueous mixture was extracted with EtOAc and then combined organic layers and evaporated under reduced pressure. The crude residue was purified by preparative TLC (DCM/MeOH, 93/7) to give 29 mg of 5-amino-6-cyano-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9](C#N)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].[Br:18]C1C=C([N+]([O-])=O)C(F)=CC=1>>[Br:18][C:9]1[CH:12]=[CH:13][C:6]([NH:5][CH2:4][CH2:3][CH:2]([CH3:17])[CH3:1])=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Product: CC(C)CCNc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
(4-Bromo-2-nitro-phenyl)-(3-methyl-butyl)-amine was prepared by the same procedure as 4-(3-methyl-butylamino)-3-nitro-benzonitrile, except using 3-bromo-6-fluoro-nitrobenzene.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[C@@H:26]([C@@H:27]([OH:39])[C@@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)[CH2:25][O:24][C:23]1([CH3:41])[CH3:40])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[C@@H:26]([C@@H:27]([OH:39])[C@@H:28]([N:38]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][C:30]2[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=2)[CH2:25][O:24][C:23]1([CH3:41])[CH3:40])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Temperature: 25 °C
Yield: 86.9 %

Procedure:
Add benzyl bromide (75 mL, 630.55 mmol) to a suspension of potassium carbonate (85 g, 615.006 mmol) and (R)-4-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (80 g, 207.25 mmol) in acetonitrile (900 mL). Heat to reflux for 16 hours, cool to room temperature, and dilute with ethyl acetate (2 L). Wash with ammonium chloride (1.5 L), saturated aqueous sodium chloride (1.5 L), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 5:95 to 20:80 ethyl acetate:hexanes) to give the desired compound as a white solid (102.1 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1ccc(CO)nc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-c3ccccn3)c2C#N)nc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:22])=[O:23])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a stirred solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(phenylsulfonyl)phenyl)propanoate (700 mg) in THF (15 mL) and water (10 mL) was added lithium hydroxide monohydrate (140 mg). The mixture was stirred at RT for 2 h. The mixture was partitioned between 0.1 N HCl(aq) and ethyl acetate, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to leave the subtitle compound (675 mg) as a white solid.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(NCC)C.CCN=C=NCCCN(C)C.Cl.[C:37]([N:44]([CH2:52][C:53]1[N:54]=[CH:55][C:56]([C:59](O)=[O:60])=[N:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:37]([N:44]([CH2:52][C:53]1[N:54]=[CH:55][C:56]([C:59]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[O:60])=[N:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1cnc(C(=O)O)cn1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1cnc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cn1
Reaction time: 1 h

Procedure:
The compound obtained in Example 8-6 (160 mg) was dissolved in DMF (3.2 ml) and diethylamine (0.32 ml) was added. After one hour, the reaction solution was concebtrated and the residue obtained was dissolved in DMF (1 ml). Then, WSCI hydrochloride (73 mg), DMAP (31 mg), and a solution of the compound obtained in Example 13-3 in DMF (1 ml) were sequentially added. After 15 hours, the reaction solution was concentrated. After the addition of chloroform and 1 mol/l hydrochloric acid, the residue was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was crude-purified by silica gel column chromatography (4 g, chloroform/ethyl acetate=1/2) to obtain the title compound (95.2 mg) as colorless syrup.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH:1]([OH:3])=[O:2].[CH2:44]([N:11]([C:10]1[C:5]([NH2:4])=[N:6][C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)=[N:8][C:9]=1[NH2:16])[C:12](=[O:15])[O:13][CH3:14])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)N(Cc1ccccc1)c1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 100 mg (0.22 mmol) of methyl {4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}carbamate formate were initially charged in THF (0.94 ml), and 44.4 mg (0.24 mmol) of a 2 N solution of sodium bis(trimethylsilyl)amide in THF were added. After 30 min at 0° C., 52 μl (0.44 mmol) of benzyl bromide were added and the mixture was stirred at 20° C. for 20 hours. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile/water (+0.1% formic acid) gradient). This gave 105 mg of the target compound (87% of theory).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]([F:30])([F:29])[F:28])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)=O.[CH3:31][NH:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CN(C=O)C>[CH3:31][N:32]([CH2:1][C:3]1[C:4]([C:27]([F:29])([F:28])[F:30])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)[CH3:33]
Reactant: CNC
Reactant: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
2-(2-(4-Formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (30 mg, 0.068 mmol), Dimethylamine (2M solution in THF, 0.169 mL, 0.34 mmol) and DMF (1 mL) were treated with acetic acid (5 drops) and sodium triacetoxyborohydride (57.2 mg, 0.270 mmol) and the mixture stirred at RT overnight. The sample was filtered and purified by preparative reverse phase HPLC followed by additional purification by SCX ion exchange chromatography to yield the title compound (13.5 mg, 0.029 mmol, 42%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])OC3C=CC=CC=3)=[CH:21][CH:20]=2)[N:9]=1.C(N(CC)CC)C.[NH2:42][CH:43]([CH3:46])[CH2:44][OH:45]>CN(C=O)C>[OH:45][CH2:44][CH:43]([NH:42][C:26](=[O:34])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=2)=[CH:24][CH:23]=1)[CH3:46]
Reactant: CC(N)CO
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CO)NC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
A solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate (110 mg, 0.23 mmol) and triethylamine (0.079 mL, 0.68 mmol) in DMF (2 mL) was added to 2-aminopropan-1-ol (1.14 mmol). The reaction was stirred at 40° C. for 2 hours then purified by prep-HPLC (basic) to give the desired material as a solid (22 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][C:13]([OH:15])=[O:14].O1CCCC1.[C:21](=O)([O:27]C(C)(C)C)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>[OH-].[Na+]>[C:23]([O:22][C:21]([N:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)CNc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc2ccccc2c1
Temperature: 24 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
To a stirred solution of 10 g (50 mM) of 2-naphthylglycine (from Preparation 1) in 100 ml of 1N sodium hydroxide were added 50 ml of tetrahydrofuran followed by 30 g (140 mM) of di-tert.-butyl carbonate. The reaction mixture was stirred at 24° C. for four hours. The product was isolated by first washing the reaction mixture three times with 50 ml portions of diethyl ether, and then the mixture was made acidic to pH 2.0 by the addition of conc. hydrochloric acid. The aqueous acid mixture was extracted several times with ethyl acetate, and the extracts were combined, washed with water, dried and the solvent was removed by evaporation under reduced pressure to provide 12.8 g (85% yield) of N-tert.-butoxycarbonyl-2-naphthylglycine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][N:34]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.37 (s, 2H), 8.14-8.12 (m, 1H), 8.07-8.03 (m, 1H), 7.90-7.86 (m, 1H), 7.41-7.38 (m, 1H), 6.93 (s, br, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: Cc1cc(C=O)cc(C)c1CCCO
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.80 g, 4.00 mmol) and 4-(3-hydroxy-propyl)-3,5-dimethyl-benzaldehyde (0.98 g, 5.1 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.80 g, 4.40 mmol) and p-TSA (0.155 g, 0.81 mmol) and the reaction mixture was heated at 115° C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered and washed with water. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give 2-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.10 g (73%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][N:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:34]1[O:36][CH2:35]1)Br.O>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH:34]1[CH2:35][O:36]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[CH:18][CH:17]=2
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (126 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare a solution. Potassium carbonate (156 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 3-(6-methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (48 mg, yield 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH:17]2[O:27][CH3:28])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][CH2:15][C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]2[O:27][CH3:28])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CCOC(=O)N1CCC(CNC(=O)c2cc(Cl)cc3c2OCCO3)C(OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@@H]1CNCC[C@@H]1CNC(=O)c1cc(Cl)cc2c1OCCO2
Yield: 51.8 %

Procedure:
A mixture of ethyl 4-[[[(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)carbonyl]-amino]methyl]-3-methoxy-1-piperidinecarboxylate (0.051 mol) and potassium hydroxide (0.5 mol) in ethanol (200 ml) was stirred and refluxed for 30 hours and then cooled. The solvent was evaporated. The residue was dissolved in water and the solvent was evaporated again. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3)93/7). The pure fractions were collected and the solvent was evaporated, yielding 9 g of (cis)-7-chloro-2,3-dihydro-N-[(3-methoxy-4-piperidinyl)methyl]-1,4-benzodioxin-5-carboxamide (interm. 3-i). Part of interm. (3-i) was dissolved in 2-propanol and converted into the ethanedioic acid salt (1:1). The precipitate was filtered off and dried, yielding 1.2 g of (cis)-7-chloro-2,3-dihydro-N-[(3-methoxy-4-piperidinyl)methyl]-1,4-benzodioxin-5-carboxamide ethanedioate (1:1) (interm. 3-j, mp. 208° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(F)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(F)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-8-fluoro-2-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([O:19]CC)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:23]>CO>[CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([NH2:23])=[O:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(CC(C)C)n(Cc2ccccc2)n1
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1cc(C(N)=O)nn1Cc1ccccc1

Procedure:
A solution of ethyl 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxylate (30 g) in methanol (60 mL) was treated with ammonium hydroxide (60 mL) according to a modification of the method described in Part D of Examples 1-4. The reaction was heated for 14 hours. At the end of the reaction, the methanol was removed under reduced pressure, and the remaining solution was extracted with tert-butyl methyl ether (3×). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Toluene was added twice and removed under reduced pressure to remove residual water. Hexane was added to the residue; crystals formed and were isolated by filtration, washed with hexane, and air-dried overnight to provide 6.93 g of 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide as small, off-white crystals.