Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH2:8][C:7](=O)[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:5]2=[O:21])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5](=[O:21])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1cccc([N+](=O)[O-])c1
Solvent: O
Product: O=c1cc(Cl)n(-c2cccc([N+](=O)[O-])c2)c(=O)n1C1CC1
Temperature: 110 °C
Yield: 34 %

Procedure:
To 1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione 5 (28 g) obtained in Step 2 was added water (3 ml), phosphorus oxychloride (72 ml) was added dropwise by small portions with stirring, and the mixture was stirred with heating at 110° C. for 1 hr. The reaction mixture was poured into ice water by small portions, and the precipitated solid was filtered by suction. The filtrate was dissolved in chloroform (300 ml), washed with water (30 ml) and brine (30 ml), and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=9:1) to give a 2:1 mixture (10 g, 34%) of 6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 and 4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7 as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.Cl[C:28]([O:30][C@@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)=[O:29].C(N(CC)CC)C>CN(C=O)C>[O:33]1[CH2:34][CH2:35][C@@H:31]([O:30][C:28](=[O:29])[NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[N:12]=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[N:10]=3)[CH2:4]2)[CH2:32]1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Yield: 54 %

Procedure:
To a solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (210 mg, 0.6 mmol) in DMF at 0° C. were added (R)-tetrahydrofuran-3-yl chloroformate (0.09 g, 0.6 mmol) and triethylamine (167 μL, 1.2 mmol) simultaneously. Ten to fifteen minutes after addition, the reaction was complete, and quenched with water, extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give (R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (150 mg, 54%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.41-8.43 (m, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.33-7.44 (m, 3H), 6.90-6.95 (m, 2H), 5.11 (dd, J=6.2, 4.6 Hz, 1H), 4.38 (t, J=14.5 Hz, 2H), 3.68-3.79 (m, 3H), 3.60-3.63 (m, 1H), 3.28-3.31 (m, 1H), 2.98-3.07 (m, 3H), 2.50 (s, 3H), 2.06-2.15 (m, 1H), 1.85-1.91 (m, 4H), 1.70 (d, J=12.9 Hz, 1H), 1.24-1.37 (m, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9](Cl)=[O:10])[CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(Cl)C1CN2CCC1CC2
Product: O=C(NC1CCN(CCc2ccccc2)C1)[C@@H]1CN2CCC1CC2

Procedure:
1-Azabicyclo[2.2.2]octane-3-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:11](=[O:20])[CH2:10][O:9][C:8]=2[CH:21]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:11](=[O:20])[CH2:10][O:9][C:8]=2[CH:21]=1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)OCC(=O)N2CCN1CCCC1
Reaction time: 4 h
Yield: 96.9 %

Procedure:
A solution of 7-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.46 g, 1.579 mmol) in dry ethanol (5 mL) was treated with Pd—C (˜0.05 g) and purged with hydrogen gas. The reaction was stirred under hydrogen atmosphere (balloon pressure) for 4 hours. The reaction was filtered through a Celite bed and washed with methanol (3×10 mL). The combined organic layers were evaporated and dried under vacuum to obtain the crude title compound (0.4 g, 97%) as a solid. 1H NMR (DMSO-d6) δ 1.61-1.70 (m, 4H), 2.44-2.56 (m, 6H, merged with DMSO-d6), 3.90 (t, 2H, J=7.2 Hz), 4.47 (s, 2H), 5.01 (s, 2H), 6.22 (d, 1H, J=2.4 Hz), 6.25 (dd, 1H, J=2.4, 8.2 Hz), 6.84 (d, 1H, J=8.7 Hz); ESI-MS (m/z, %): 262 (MH+, 100), 191 (44).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: N#Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C#N)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-cyano-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=402.37.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:34](Cl)(=O)[NH2:35].[C:38](=[O:41])(O)[O-:39].[Na+].C(Cl)Cl.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C1COCC1>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:1][N:2]([CH2:3][CH2:34][NH2:35])[C:38](=[O:41])[O-:39]
Reactant: O=C([O-])O
Reactant: NC(=O)Cl
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CCN)C(=O)[O-]
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Oxycodone free base (6.5 g, 20.6 mmol) was dissolved in dry, degassed tetrahydrofuran (120 mL), and the mixture was cooled to −10° C. using a dry ice/acetone bath. Potassium bis(trimethylsilyl)amide (KHMDS) (103.0 mL, 51.6 mmol, 0.5 M in toluene) was added via cannula. The mixture was stirred under N2 at below −5° C. for 30 min. N,N-Bis(tert-butyl) N′-2-(chlorocarbonyl(methyl)amino)ethylcarbamate (8.0 g, 23.7 mmol), (Compound C) in THF (30 mL) was then added via cannula over 15 min. The mixture was stirred at −5° C. for 30 min. Another portion of carbamoyl chloride (4.0 g, 11.9 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 h. Sodium bicarbonate (10 mL, sat. aq.) was added. The mixture was concentrated under vacuum to half of its initial volume. EtOAc (50 mL) was added, and layers were separated. The organic phase was further washed with water (3×20 mL) and brine (40 mL), and then was concentrated. The residue was purified by silica gel chromatography, using DCM/MeOH (gradient 100/1 to 100/15) to afford a white foam in 55% yield (7.0 g, 13.4 mmol). This material was dissolved in a 1:1 mixture of DCM/trifluoroacetic acid (TFA) (20 mL/20 mL) at room temperature and stirred for 1 h. The solution was then concentrated under vacuum to afford a TFA salt of oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate (Compound KC-19) as a thick oil (7.3 g, 11.4 mmol, 99% purity). MS: (m/z) calc: 415.2, observed (M+H+) 416.5.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:12][C:2]([F:1])([F:11])[C:3]1[CH:4]=[C:5]([OH:7])[C:20]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:21]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(N)cc1
Product: COc1ccc2nc(C(F)(F)F)cc(O)c2c1

Procedure:
Ethyl trifluoroacetoacetate and 4-methoxyaniline were reacted together in presence of polyphosphoric acid to give 2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (cf. Jouillie and Dey). The latter was converted to 2-trifluoromethyl-4-chloro-6-methoxy-quinoline by analogy with Example IV. This was in turn converted first to 2-trifluoromethyl-6-methoxyquinoline by hydrogenation in the presence of palladium on charcoal and thence to 2-trifluoromethyl-6-hydroxyquinoline by reaction with aqueous hydrobromic acid. The latter was reacted with (8-bromo-1-tetrahydro pyranyloxy)octane according to Example BIII, 8(2-trifluoromethyl-6-quinolinyloxy)octane-1-ol was prepared and used in Stage b.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>>[Si:21]([O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1Cc2ccc(O)cc2CN1
Agent: Cl
Product: COC(=O)[C@H]1Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2CN1
Yield: 79 %

Procedure:
Prepared as in Example 1c-JF from (R)-methyl 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (Example 13-2c) and tert-butylchlorodimethylsilane. Yield 79%, yellow oil (1.15 g, 79%). MS 322 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5](Br)[CH2:6][CH3:7])[CH3:2].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C(Br)CC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)OCc1ccccc1

Procedure:
As per scheme-12, ethyl-2-bromobutyrate (12-a) is reacted with benzyl alcohol in presence of potassium hydroxide in DMF at 25° C. to 35° C. up to 3 hr to provide ethyl-2-benzyloxybutyrate (12-b). Compound 12-b is treated with hydrazine hydrate in ethanol at reflux temperature to provide corresponding acid hydrazide compound 12-c. The compound 12-c is treated with 2-picolinic acid in the presence of dehydrating agent EDC along with HOBt and N-methyl morpholine in DMF at a temperature 0° C. to 30° C. for 1 hr to provide uncyclized compound 12-d. The compound 12-d is further treated with Lawesson's reagent in tetrahydrofuran at a reflux temperature for 4 hr to provide corresponding pyridinyl-1,3,4-thiadiazolyl compound 12-e. The compound 12-e is stirred with borontribromide in dichloromethane at a temperature ranging from 0° C. to 5° C. for 1 hr followed by at 35° C. for overnight, to provide corresponding pyridinyl-1,3,4-thadiazolyl propanol compound 12-f. The compound 12-f is treated with p-nitrophenylsulfonyl chloride in the presence triethylamine in a dichloromethane at a temperature ranging from 0° C. to 15° C. to provide corresponding p-nitrophenyl sulfonic acid ester compound 12-g.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[CH2:36]([O:35][CH2:34][C@H:16]([NH:15][C:12](=[O:14])[CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH:2]([CH3:3])[CH3:4])[CH2:10][CH2:9]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CC(C)N1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 45.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-isopropylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound III, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-isopropylpiperazin-1-yl)acetamido)propanamide (19.8 mg, 45.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.92 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.77 (m, 1H), 3.71 (m, 1H), 2.96 (d, 2H), 2.61 (m, 1H), 2.50 (t, 8H), 0.95 (d, 6H). MS (EI) for C31H37FN4O4. found 549.7 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:39])[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([CH:37]=O)=[CH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])[CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[C:9]([O:13][C:14](=[O:39])[NH:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]([CH2:37][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])[CH2:20][CH2:21]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc2ncc(Cl)c(C=C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2ncc(Cl)c(C=C(CNCc3ccccc3)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzylamine (360 mg, 3.36 mmol, 3.0 eq) is added at room temperature to a stirred solution of {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester (500 mg, 1.12 mmol, 1.0 eq) in ethanol (20 mL), followed by acetic acid (337 mg, 5.61 mmol, 5.0 eq) and sodium cyanoborohydride (352 mg, 5.61 mmol, 5.0 eq). After 2 hours stirring at room temperature, the reaction mixture is extracted with ethyl acetate (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 3:1 to 1:1, v/v) to afford {trans-4-[1-(benzylamino-methyl)-2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (320 mg, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:8]=2)[N:3]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][Cl:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1-c1ccc2nc(Cl)c(CO)cc2c1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc2nc(Cl)c(CCl)cc2c1
Reaction time: 0.25 h

Procedure:
A mixture of (6-bromo-2-chloroquinolin-3-yl)methanol (19.8 g, 72.5 mmol, prepared as in example 2, step 2), o-tolylboronic acid (10.4 g, 76.1 mmol), potassium acetate (21.3 g, 217.4 mmol) and dichlorobis(4-(di-tert-butylphosphino)-N,N-dimethylaniline)palladium (II) (0.51 g, 0.72 mmol) in CH3CN (300 ml) and water (100 ml) was heated in to reflux. After 2 h, the reaction was allowed to cool to RT and the aqueous phase was discarded. The organics were washed with 2×50% brine/water, and then 2× brine. The organics were concentrated to ˜100 mL, at which point the precipitate was filtered off to afford a pale yellow solid of (2-chloro-6-o-tolylquinolin-3-yl)methanol. Step 2: (2-chloro-6-o-tolylquinolin-3-yl)methanol (13.9 g, 49.0 mmol) was treated with DCM (100 ml) and thionyl chloride (106 ml, 1456 mmol) at ambient temperature. After 15 min, the solution was concentrated and azeotroped with 2×100 mL toluene, to afford a yellow solid of 2-chloro-3-(chloromethyl)-6-o-tolylquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[K].[CH2:36]([NH:43][S:44](=[O:47])(=[O:46])[NH2:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:5]=[C:6]([NH:45][S:44](=[O:46])(=[O:47])[NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: NS(=O)(=O)NCc1ccccc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
4-[4,6-Dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carbonitrile (3.2 g) was dissolved in DMSO (20 ml), N-ethyidiisopropylamine (1.7 ml) and benzylsulfamic acid amide potassium salt (3.52 g) was added. The mixture was stirred for 18 h at rt, poured onto ice/water, acidified with solid citric acid and the precipitate was filtered off and recrystallized form EtOAc to give benzylsulfamic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (4.17 g). LC-MS: tR=5.55; [M+H]+=523.29.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:25])(=O)=O)C=CC=CC=1.O.Cl>C(O)C.C(COC)OC>[CH3:25][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[C:16]([C:21]([F:23])([F:22])[F:24])[CH:17]=[CH:18][CH:19]=2
Reactant: Cc1cc2c(C(F)(F)F)cccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Yield: 79.3 %

Procedure:
0.271 ml of 5N sodium hydroxide is added to a solution of 460 mg of 1-benzenesulfonyl-2-methyl-4-trifluoromethyl-1H-indole in 1.4 ml of ethanol and 0.44 ml of dimethoxyethane. The reaction mixture is maintained at reflux for 6 hours and poured into water acidified with a hydrochloric acid solution until pH=1 and extracted with ethyl acetate. The organic phases are combined and washed with a 10% sodium bicarbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 214 mg of 2-methyl-4-trifluoromethyl-1H-indole, in the form of a pale yellow oil, which is used in the next step.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([C:18](=[O:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1>O1CCCC1.[Pd]>[C:18]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)C1Cc2ccccc2N(Cc2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)C1CNc2ccccc2C1

Procedure:
868 mg of 1-benzyl-3(R,S)-acetyl-1,2,3,4-tetrahydroquinoline are hydrogenated to saturation in 100 ml of tetrahydrofuran in the presence of 100 mg of palladium-on-charcoal (10% of Pd) under normal pressure at room temperature. The reaction mixture is filtered and the concentrated filtrate is purified by means of FC over 50 g of silica gel (mobile phase B). This gives the title compound: Rf (A)=0.29; Rf (D)=0.08.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxy-N-tert-butoxycarbonyl-proline methyl ester (5.89 g, 24 mmol) and triethylamine (4 mL, 28.8 mmol) in dichloromethane (80 mL) was cooled to 0° C. and treated with methylsulfonyl chloride (2.1 mL). After stirring an additional 2 h, the reaction mixture was acidified with 2% HCl (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed successively with sat. aq NaHCO3, and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave 4-methylsulfonyloxy-N-tert-butoxycarbonyl-proline methyl ester. 1H NMR (CDCl3), 5.25 (m, 1H), 4.41 (m, 1H), 3.78 (m, 5H), 3.06 (s, 3H), 2.61 (m, 1H), 2.22 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]C(=O)C)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[SH:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: CC(=O)SCCc1ccc(OS(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(CCS)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
Thioacetic acid S-[2-(4-methanesulfonyloxy-phenyl)-ethyl]ester (250 mg, 0.91 mmol) was dissolved in anhydrous THF (2.5 mL) and LiAlH4 (38 mg, 1.0 mmol) was added in portions. After completed addition the mixture was warmed up to 50° C. and stirred for 1.5 h. The mixture was cooled down to 0° C. and excess LiAlH4 was hydrolyzed by the addition of H2O (0.8 mL), 2N aq. NaOH (1.0 mL) and THF (10 mL). Afterwards the reaction mixture was refluxed for 30 min then the precipitated salts were filtered off and the remaining filtrated was diluted with EtOAc. After extraction with brine and drying over Na2SO4, the solvent was evaporated under reduced pressure to afford the crude product as an oil (232 mg, 94.9%). 1H NMR (400 MHz, CDCl3): δ 7.29-7.31 (d, 2H), 7.21-7.23 (d, 2H), 3.31 (s, 3H), 2.81-2.85 (m, 2H), 2.68-2.73 (m, 2H).