Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:5])[CH3:2].[C:15]([O-])(=[O:17])[CH3:16].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.CCCCCON=O>C(Cl)(Cl)Cl>[C:15]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14][CH:13]=2)[CH:9]=[N:10]1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)c1ccc2[nH]ncc2c1
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCCON=O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc2c(cnn2C(C)=O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
5-Ethoxycarbonylindazole. A mixture of the product prepared according to Example E-19 Part B (250.55 g, 1.4 mol), potassium acetate (143.3 g, 1.46 mol), acetic anhydride (285.9 g, 2.8 mol) and chloroform (ethanol-free; 2700 mL) was stirred at room temperature. The temperature rose to 40° C., then started to decline, at which time no starting material was detected by TLC. A mixture of 18-crown-6 (75 g, 280 mmol) and n-amyl nitrite (364.5 g, 3.1 mol) was added and the mixture was heated at reflux overnight. The cooled mixture was washed with saturated aqueous sodium bicarbonate, then with water, and was dried (MgSO4), filtered and concentrated. The residue was combined with that from another batch (711.3 g) and distilled through a 10 cm vigreaux column under vacuum to provide 1-Acetyl-5-ethoxycarbonyl-indazole (576 g, 82%), bp 115-165 ° C. (1.0 Torr). This intermediate was combined with hydrochloric acid (6N; 2000 mL) and ethanol (2000 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the solid was combined with water. The pH of the mixture was adjusted to 8 with aqueous ammonia, and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated to provide a solid (460 g). This was recrystallized from acetonitrile (1000 mL), and the crystals were washed with ethanol, then hexane, and dried to provide the title product (281 g, 60%) as a tan solid, mp 122-124° C.: 1H NMR (CDCl3) d 10.23 (bs, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.53 (d, 1H), 4.42 (q, 2H), 1.42 (t, 3H); High resolution mass spectrum (NH3-CI) calculated (M+H+) 191.0821, found 191.0838.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H].O1CCOCC1.Cl>CN(C)C=O.CO.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13]
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@H](C)N)C2
Yield: 72.1 %

Procedure:
The compound obtained in Example 224 (3.0 g, 6.9 mmol) was dissolved in dimethylformamide (200 ml). To the obtained solution, 10% palladium-on-carbon (3.0 g) was added, followed by stirring at room temperature overnight in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was dissolved in methanol (20 ml), and 4N-HCl dioxane (4 ml) was added thereto while cooling on ice. The mixture was condensed under reduced pressure. The resultant residue was recrystallized from methanol--ether to obtain 1.5 g of the title compound as pale yellow powdery crystals (64.4%).
Reaction SMILES: [SH:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([CH3:16])([SH:15])[CH3:14].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][S:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([SH:15])([CH3:16])[CH3:14]
Reactant: CI
Reactant: CC(C)(S)CNc1ccccc1NCC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(C)(C)CNc1ccccc1NCC(C)(C)S
Reaction time: 1 h
Yield: 79.1 %

Procedure:
1,2-Bis (2-Mercapto-2-methylpropylamino)benzene (0.47 g, 1.69×10-3 mol), and 0.09 g (1.85×10-3 mol, 110 M%) sodium hydride were dissolved in 25 ml tetrahydrofuran. Methyl iodide (0.080 ml, 1.27×10-3 mol, 75 M%) was added, and the mixture was stirred under nitrogen for 1 hour. The excess hydride was destroyed by the slow addition of 10 ml 0.5 M HCl. The mixture was shaken with a mixture of 100 ml ether and 100 ml 0.5 N HCl. The aqueous layer was extracted with an additional 50 ml portion of ether, and the combined ether layers were washed with 100 ml saturated NaCl. The ether layer was then dried over anhydrous Na2SO4. Rotary evaporation yielded 0.30 g (94% yield) of 1-[2-methylthio-2 -methylpropylamino]-2-(2-mercapto-2-methylpropylamino)benzene as a yellow oil. Isolation was performed by radial chromatograph on a 1 mm silica plate, using petroleum ether: ethyl acetate-80:20 as the eluting solvent to give yielding a mixture of the 1-[2-methylthio-2-methylpropyl- amino]-2-(2-mercapto-2-methylpropylamino)benzene, S,S'-dimethyl, and the dithiol starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:26][OH:27])[C:12]([CH3:25])=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[H-].[Na+].C[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[CH:41](Br)[CH3:42])=[CH:35][CH:34]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:26][O:27][CH:41]([CH3:42])[C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([OH:45])=[O:31])=[CH:34][CH:35]=2)=[O:44])[C:12]([CH3:25])=[N:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1CO
Reactant: COC(=O)c1ccc(NC(=O)C(C)Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1COC(C)C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 80 mg of [5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in 2 ml of DMF were added 38 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min, 71 mg of tetrabutylammonium iodide and 83 mg of 4-(2-Bromo-propionylamino)-benzoic acid methyl ester were added and the reaction mixture was heated to 80° C. for 8 h. After cooling to room temperature and dilution with 1 M aqueous hydrochloric acid the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 2 mg.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=2)=[CH:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: OCCc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: OCCc1ccc(C2CCNCC2)cc1
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To a solution of 8.0 g of 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenethyl alcohol in ethanol (200 ml) was added 15 g of 10% palladium-carbon (moisture content: 50%) and hydrogenation was effected at ordinary temperature under atmospheric pressure for 12 hours. After the completion of the reaction, the palladium-carbon was filtered off and the filtrate was distilled under reduced pressure to thereby give 4.0 g of crude 4-(piperidin-4-yl)phenethyl alcohol as a colorless oily substance. To 4.0 g of this crude product and 3.3 ml of triethylamine dissolved in dichloromethane (30 ml) was added 3.1 ml of benzyl chloroformate at 0° C. and the mixture was reacted at room temperature for 1 hour. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.0 g of the title compound as a yellow oily substance.
Reaction SMILES: C(O/[N:5]=[C:6](\[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=3[O:15][N:5]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(/C(=N/OC(C)=O)c2ccc(Cl)cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 80 °C

Procedure:
A mixture of 5.32 g of E-4'-chloro-2-hydroxy-4-methoxybenzophenone-O-acetyl oxime, 3.45 g of potassium carbonate and 50 ml of 2-butanone is heated under reflux at 80° C. for 2 hr. The reaction mixture is poured into water/ice. The precipitate is filtered, dried, and recrystallized from toluene/ether to give 3-(4-chlorophenyl)-6-methoxy-1,2-benzisoxazole, mp 148°-9° C.
Reaction SMILES: CS([O:5][CH:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[Cl:16])[CH3:7])(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]([N+:35]([O-])=O)[C:21]([CH:24](C(OCC)=O)[C:25](OCC)=O)=[N:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:17][C:18]1[CH:19]=[C:20]2[N:35]([O:5][CH:6]([C:8]3[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=3[Cl:16])[CH3:7])[CH:25]=[CH:24][C:21]2=[N:22][CH:23]=1
Reactant: CC(OS(C)(=O)=O)c1c(Cl)ccc(F)c1Cl
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Yield: 78 %

Procedure:
A solution of 1-(2,6-dichloro-3-fluorophenyl)ethyl methanesulfonate (4.39 g, 15.3 mmol, 1.0 eq), 6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol (prepared as in example 1: 3.92 g, 20.0 mmol, 1.3 eq) and K2CO3 (6.34 g, 45.9 mmol, 3.0 eq) in 90 ml of N,N-dimethylformamide (DMF) was stirred at room temperature overnight. The solid was filtered out and the solvent evaporated. The residue was dissolved in DCM, and the solution was washed with water and brine, dried, evaporated and chromatographed (MeOH/DCM 1:20) to give a light yellow oil, 4.63 g, in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:16])[CH:9]=[C:8]2[C:17](O)=[O:18])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:45]([NH:52][C:53]([CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CCOC(C)=O.CN(C=O)C>[CH2:45]([NH:52][C:53]([CH:55]1[CH2:60][CH2:59][N:58]([C:17]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:16])=[O:18])[CH2:57][CH2:56]1)=[O:54])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Reactant: Cc1cccc2cc(C(=O)O)n(Cc3ccc(Cl)cc3)c12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1cccc2cc(C(=O)N3CCC(C(=O)NCc4ccccc4)CC3)n(Cc3ccc(Cl)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The following was added to sequentially to DMF (2 mL): 1-(4-chlorobenzyl)-7-methyl-1H-indole-2-carboxylic acid (50 mg, 0.167 mmol), DIPEA (0.10 mL, 0.584 mmol), EDC (38 mg, 0.200 mmol), and HOBT (31 mg, 0.200 mmol). This was allowed to stir for 30 min at rt, after which time the crude N-benzylpiperidine-4-carboxamide (˜36 mg, 0.20 mmol) was added. The reaction was stirred at rt for 18 h, at which time the reaction was diluted with 1:1 EtOAc:diethyl ether and washed with 10% aq. sodium carbonate (2×), dried over magnesium sulfate, and concentrated. The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes) to afford the title compound as a white powder. (Yield: 39 mg, 0.078 mmol, 47%) 1H NMR (400 MHz, CDCl3) 7.50, 7.38-7.26, 7.18, 7.05-6.97, 6.81, 6.63, 5.72, 5.66-5.57, 4.70-3.89, 4.44, 2.86-2.66, 2.57, 2.32-2.23, 1.77
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[NH:27][CH2:26][CH2:25][CH2:24]3)=[O:16]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[N:27]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:26][CH2:25][CH2:24]3)=[O:16]
Reactant: COC(=O)c1cccc2c1[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 43 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 43% of theory; TLC: rf=0.30 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.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>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:35]=[C:34]([O:33][CH3:32])[C:39]=1[O:40][CH3:41]
Reactant: CC(=O)NCc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(CNC(C)=O)cc4)c3c2)cc(OC)c1OC
Yield: 53.1 %

Procedure:
N-{4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzyl}-acetamide (Intermediate CC, 24 mg, 0.048 mmol), 3,4,5-trimethoxyphenyl boronic acid (13 mg, 0.058 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.002 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (2 ml) and heated in a microwave reactor at 150° C. for 20 min. EtOAc was added, washed with water, dried and purified by silica gel chromatography eluting with 0-4% MeOH:DCM to give 11 mg (53%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH2:40][CH2:41][CH:42]1[CH2:44][CH2:43]1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:40][CH2:41][CH:42]2[CH2:44][CH2:43]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: NCC1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCC2CC2)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and (aminomethyl)cyclopropane.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1>>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:24])[CH3:25])=[N:20][N:21]=4)[CH:18]=3)[CH2:4][CH2:3]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)C(C)C
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12)C(C)C

Procedure:
The title compound was prepared starting from Intermediate 103c and Intermediate 95c using analogous procedures to those described in Intermediate 95d. LCMS (Method 4): Rt 3.92 min, m/z 765 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[CH:33](=O)[CH2:34][OH:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][N:28]([CH2:33][CH2:34][OH:35])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CNCC3)c1
Reactant: O=CCO
Product: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(CCO)CC3)c1
Yield: 13 %

Procedure:
2-(4-(3-Methoxybenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (19.6 mg, 13%) was synthesised from 4-(3-methoxybenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 53a) and glycolaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 471.3 (M+H)+
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH2:45][CH:46]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43]>C(Cl)Cl>[C:27]([O:26][C:25]([NH:24][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@H:9]([OH:23])[CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)[C:42]([O:44][CH2:45][CH:46]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:52]=2[C:53]2[C:58]1=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:43])=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(CNC[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)cc(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN(C[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)OCC2c3ccccc3-c3ccccc32)cc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of tert-butyl (2S,3R)-1-cyclohexyl-4-(3,5-dimethoxybenzylamino)-3-hydroxybutan-2-ylcarbamate (66.5 mg, 0.153 mmol) in CH2Cl2 (10 mL) at 0° C. was added DIEA (1.5 mL) followed by 9-fluorenylmethyl chloroformate (39.5 mg, 0.153 mmol) and the resulting mixture was stirred at 0° C. for 2 h and at rt for 2 h. The reaction mixture was concentrated and the residue was diluted with EtOAc and water. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel to provide (2R,3S)-3-(t-butoxycarbonylamino)-4-cyclohexyl-1-(N-(3,5-dimethoxybenzyl)-N-((9H-fluoren-9-yl)methoxycarbonyl)amino)butan-2-ol (78.5 mg, 78%). 1H NMR: 0.79 (m, 1H), 0.95 (m, 1H), 1.06-1.38 (m, 6H), 1.42 (s, 9H), 1.56-1.70 (m, 6H), 1.83 (m, 1H), 3.25-3.50 (m, 2H), 3.70 (m, 1H), 3.73 (s, 6H), 3.85 (m, 1H), 4.22 (m, 1H), 4.29-4.70 (m, 5H), 6.35 (m, 3H), 7.20 (m, 1H), 7.32-7.48 (m, 4H), 7.58 (m, 1H), 7.69 (m, 1H), 7.75 (m, 1H). MS (E/Z): 659 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]([NH:25][NH2:26])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[CH2:15]([O:22][C:23]([NH:25][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 57 %

Procedure:
To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g), benzylhydrazinecarboxylate (16.7 g), DCM (150 mL), and acetic acid (5.75 mL) was added sodium triacetoxyborohydride (31.9 g), followed by stirring at room temperature for 2.5 days. To the reaction liquid was added water, and the organic phase was separated. The aqueous phase was extracted with chloroform, and the combined organic phase was washed with water, a saturated aqueous sodium bicarbonate, and saturated brine in this order, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain tert-butyl 4-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (10.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N12CCN(CC1)CC2.CN(C)C=O.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O>[CH3:27][N:28]([C:29](=[S:30])[O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:32]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1OC(=S)N(C)C
Temperature: 50 °C
Reaction time: 7 h
Yield: 76.5 %

Procedure:
To a mixture of 350 g of methyl 2-hydroxy-4-methoxybenzoate, 648 g of 1,4-diazabicyclo[2.2.2]-octane (DABCO) and 3 L of dimethylformamide was added 712 g of dimethylthiocarbamoyl chloride. The mixture was warmed to 50° C. and held for 7 hours, then allowed to cool overnight. The mixture was poured into 10 L water; the aqueous mixture was extracted with 8 L of benzene-hexane (4:1). The organic solution was washed with 1N HCl, 10% NaOH, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 396 g of the title compound, m.p. 95°-105° C. Further extraction of the aqueous mixture gave additional product, 171 g, m.p. 117°-120° C. Recrystallization of a portion of the crude product from methanol gave pure material, m.p. 122°-124° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)=[CH:3][CH:2]=1.S(Cl)([Cl:15])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Cl:15])=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccncc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCCCCCc1ccncc1
Yield: 93.4 %

Procedure:
A solution of 5-(4-pyridinyl)-1-pentanol (3.71 g, 0.0225 mol) in 50 mL of chloroform is treated with thionyl chloride (5.4 g, 0.0449 mol) in 25 mL of chloroform. The resulting solution is neutralized with a saturated solution of sodium bicarbonate and extracted with chloroform. The organic phase is dried (sodium sulfate) and evaporated in vacuo to give 3.86 g of 5-(4-pyridinyl)-1-pentylchloride as a brown oil.