Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2occc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)CCO2
Yield: 85 %

Procedure:
A solution of 5-fluorobenzofuran and 10% palladium on carbon in acetic acid (25 ml) was hydrogenated under 50 psi for 12 hours. The catalyst was filtered through celite and the celite was washed with methylene chloride (200 ml). The organic layer was washed with 1N NaOH (3×100 ml) and brine (3×100 ml) and dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afforded 2.59 g (85%) of product as a clear oil: 1H NMR (300 MHz, CDCl3): δ3.12 ppm (t, 2H, J=8.7 Hz), 4.58 (t, 2H, J=8.7 Hz), 6.68 (dd, 1H, J=8.7, 4.2 Hz), 6.79 (tm, 1H, J=8.7 Hz), 6.89 (dm, 1H, J=8.1 Hz).
Reaction SMILES: [C:1]([NH:9][C:10](=[S:23])[NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]([Br:22])[CH:13]=1)(=O)[C:2]1C=CC=CC=1.O1CCCC1.[OH-].[K+].Cl.CO>CO>[Br:22][C:14]1[CH:13]=[C:12]([NH:11][C:10]2[S:23][CH:2]=[CH:1][N:9]=2)[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=1
Reactant: COC(=O)c1cc(Br)cc(NC(=S)NC(=O)c2ccccc2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Br)cc(Nc2nccs2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2.37 g of methyl 6-(3-benzoylthioureido)-4-bromopyridine-2-carboxylate, 20 ml of tetrahydrofuran and 40 ml of methanol was added 673 mg of potassium hydroxide. The reaction mixture was stirred at room temperature for 1.5 hours, and acidified with a hydrochloric acid-methanol solution. The solvents were concentrated in vacuo. The resulting residue was dissolved in 60 ml of 1,4-dioxane and 3.53 ml of a 40% chloroacetaldehyde aqueous solution was added thereto. After the reaction mixture was heated under reflux for 1 hour, 40 ml of a hydrochloric acid-methanol solution and 60 ml of methanol were added thereto at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized from methanol-diethyl ether to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:29]2[N:30]([CH3:34])[C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)=[O:36])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc3cc(F)ccc3n2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.98 min; [M+H]+=503.4.
Reaction SMILES: COC(C1CCN(S(C[C:15]2[C:24]3C(=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18](CC)[C:17](C)(C)[CH:16]=2)(=O)=O)CC1)=O.[CH3:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[CH:33]([CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH2:32][C:31]1([CH3:48])[CH3:47].C(N)CCCCCCC.C(Cl)(Cl)Cl>C(#N)C.C(O)C>[CH3:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[CH:33]([CH2:42][S:43]([NH:18][CH2:17][CH2:16][CH2:15][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])(=[O:45])=[O:44])[CH2:32][C:31]1([CH3:48])[CH3:47]
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Reactant: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)Cl
Solvent: CCCCCCCCN
Solvent: CCO
Solvent: CC#N
Product: CCCCCCCCNS(=O)(=O)CC1CC(C)(C)N(C)c2cc(OC)ccc21
Yield: 69 %

Procedure:
(1-Methyl-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroquinol-4-yl)-N-octyl-methane-sulfonamide (21) is prepared similarly to compound (10) from compound (19) and n-octylamine in dry acetonitrile. It is isolated by column chromatography on silica gel using a gradient running from chloroform to ethanol.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[F:31][C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]2[CH2:40][O:39]2)=[CH:34][CH:33]=1>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:40][C@H:38]([OH:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(F)cc3)cc2)CC1
Yield: 21 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.400 g, 0.95 mmol) was reacted with (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.119 g, 0.713 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.085 g, 0.15 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:24]([CH:27]1[NH:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]1=[O:34])([CH3:26])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH:27]([CH:24]([CH3:25])[CH3:26])[C:28](=[O:34])[N:29]([CH3:33])[C:30]4=[O:32])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)C1NC(=O)N(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C(C)C)cc3)CC2)c(C)c1
Yield: 52.7 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 5-isopropyl-3-methylimidazolidine-2,4-dione (69 mg) described in Preparation Example 216 and by the reaction and treatment in the same manner as in Example 536, the title compound (95 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:7]([NH2:9])=[O:8])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(N)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1cc(C(N)=O)ccc1N
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Palladium on carbon (5%, 0.510 g) was added into a solution of 3-ethoxy-4-nitro-benzamide (1.694 g, 8.06 mmol) and ammonium formate (2.17 g, 34.4 mmol) in MeOH (25 mL) at ambient temperature. The solution was stirred for 1 hour, filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo and triturated from diethyl ether to yield white solid (1.45 g, 100%).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:22][S:23]([NH:26][C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:24].C(N(CC)CC)C.[Cl-].[Li+]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:22][S:23]([NH:26][C:27]1[CH:28]=[C:29]([C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[C:10]3[N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:5][CH:4]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Nc1cccc(Br)c1
Reactant: CN1CCN(c2cccc3ccc([Sn](C)(C)C)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(-c4cccc(NS(C)(=O)=O)c4)cc23)CC1
Yield: 35 %

Procedure:
The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methylsulfonylamino-1-bromobenzene (0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours. The product was obtained in 35% yield. A sample was obtained by recrystallization from ethyl acetate for analysis: mp 100°-101 ° C. Analysis calculated for C22H25N3O2S·1.5 H2O: C, 62.54; H, 6.68; N, 9.94. Found: C, 62.70; H, 6.46; N, 9.89.
Reaction SMILES: O.Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:21][C:22]2[S:26][C:25]([Cl:27])=[N:24][C:23]=2[Cl:28])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]1)=O)(C)(C)C>C1COCC1>[CH3:19][CH:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][C:23]=1[Cl:28])[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Reaction time: 0.67 h
Yield: 94.8 %

Procedure:
To a mixture of water (850 ml) and concentrated hydrochloric acid (240 ml) is added a solution of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester (304.5 g, 0.72 mol) in THF (600 ml) dropwise at 65° C. The addition and reaction are complete in 40 minutes. THF is then stripped under vacuum; residual aqueous layer is extracted with 2 L MTBE (to remove remaining (2,4-dichloro-thiazol-5-yl)-methanol). Neutralized by addition of NaOH (30%, 200 ml) and extracted twice with MTBE (1.5 L). Combined organic layers are washed with brine (3 L) then clarified (to remove insoluble). The organic layer is then concentrated under vacuum to afford 220 g of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine as a pink powder. Yield 95% (HPLC=99% area). Mass spectrum (ion spray): m/z=322 (M+1); 1H NMR (400 MHz, CDCl3): δ=3.73 (2H, s), 3.17 (2H, m), 2.56 (3H, m). 2.31 (2H, d), 2.17 (1H, s, NH), 1.76 (2H, m), 1.68 (1H, m), 1.46 (2H, m), 0.92 (6H, d); 13C NMR (100 MHz, CDCl3): δ=20.6, 27.09, 28.88, 46.39, 47.20, 58.10, 58.52, 131.88, 137.30, 150.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[O:32]([CH2:39][CH2:40][NH2:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:41][CH2:40][CH2:39][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.93 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>ClCCl>[C:23]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCc1ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2ccccc2C2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 126.3 %

Procedure:
tert-Butyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate 6a (2.128 g, 6.28 mmol) was dissolved in anhydrous dichloromethane (30 mL), cooled in an ice-H2O bath and treated dropwise with a solution of acetyl chloride (518 mg, 6.59 mmol) in anhydrous dichloromethane (5 mL). The reaction was then treated dropwise with a solution of triethylamine (1.335 g, 13.2 mmol) in anhydrous dichloromethane (5 mL). The reaction was stirred in the ice-H2O bath for 15 minutes, then diluted with dichloromethane (100 mL), washed with H2O, saturated NaHCO3 (3×), saturated brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to afford crude tert-butyl 2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate 6b as a colorless oil (2.732 g, quantitative yield). LC/MS m/z [M+H]+ 345.2 retention time 2.98 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:27]=[CH:26][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)(=[O:19])=[O:18])=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH2:31][CH2:30]1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cn2)CC1

Procedure:
Prepared according to Procedure C from 6-chloro-4-(4-phenylsulphonylanilino)pyrido[3,4-d]pyrimidine and 1-methylpiperazine; δH (CDCl3+DMSO) 9.66 (1H,s), 8.91 (1H,s), 8.52 (1H,s), 8.15 (2H, d), 7.88-7.98 (4H,m), 7.48-7.62 (4H,m), 3.66-3.74 (4H,m), 2.52-2.64 (4H,m), 2.38 (3H,s); m/z (M+1)+461.
Reaction SMILES: Cl.[N:2]1([CH2:7][C@@:8]2([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][C:53]=3[F:59])[O:12][CH2:11][C@@H:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:32]=[CH:31][C:30]([N:33]6[C:37](=[O:38])[N:36]([C@H:39]([CH2:50][CH3:51])[C@@H:40]([O:42]CC7C=CC=CC=7)[CH3:41])[N:35]=[CH:34]6)=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:9]2)[CH:6]=[N:5][CH:4]=[N:3]1>CO.[Pd]>[CH3:51][CH2:50][C@H:39]([N:36]1[N:35]=[CH:34][N:33]([C:30]2[CH:31]=[CH:32][C:27]([N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@@H:10]5[CH2:11][O:12][C@:8]([C:52]6[CH:57]=[CH:56][C:55]([F:58])=[CH:54][C:53]=6[F:59])([CH2:7][N:2]6[N:3]=[CH:4][N:5]=[CH:6]6)[CH2:9]5)=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)=[CH:28][CH:29]=2)[C:37]1=[O:38])[C@@H:40]([OH:42])[CH3:41]
Reactant: CC[C@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC[C@@H]([C@H](C)O)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 30 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
5N hydrochloric acid (72 ml) and 10% Pd—C(10 g) were added to a solution of 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3R)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one compound of formula-21 (42 g) in methanol (420 ml). The reaction mixture was hydrogenated for 5 hours under a hydrogen gas pressure of 4-5 kg/cm2 at 50°. After completion of reaction, the catalyst was filtered off and washed with methanol. pH of the filtrate was adjusted to ˜7.0 using 4N sodium hydroxide. Water was added to the reaction mixture and stirred for 2 hours at 25-35° C. Filtered the separated solid and washed with water. The obtained solid was dissolved in acetone (320 ml) and stirred at reflux temperature for 30 minutes. Filtered the undissolved product and added water to the filtrate and stirred the reaction mixture for 4 hours at 25-35° C. Filtered the separated solid and washed with water. Further the solid was recrystallized from isopropyl alcohol to get the title compound. Purity by HPLC: 99.85%; Yield: 75.0%: Chiral purity by HPLC: 99.82%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][C:43]=1[C:50]([F:53])([F:52])[F:51]>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([O:22][C:42]3[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][C:43]=3[C:50]([F:51])([F:52])[F:53])[CH:19]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3C(F)(F)F)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 50.5 %

Procedure:
Using 0.46 g (0.82 mmol) of {4-[3-[4-tert-butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 4-fluoro-3-tri-fluoromethylbenzonitrile (0.313 g, 1.65 mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required product. NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (18H, d), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.75 (1H, d), 7.02 (1H, s), 7.08 (2H, d), 7.20 (1H, d), 7.28 (2H, d), 7.41 (3H, m), 8.1 (1H, m), 8.38 (2H, m).
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[O-:11].[Na+].S([O-])([O-])=O.[Na+].[Na+].[C:19](=[O:21])=[O:20]>CC1(C2C=CC=CC=2)C2C(=CC=CC=2)CC1>[OH:11][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C=O
Agent: CC1(c2ccccc2)CCc2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O

Procedure:
204 parts of technical sodium β-naphtholate melt containing 100 parts of sodium-β -naphtholate and 100 parts of sodium sulfite is stirred at 250° to 260° C. with 150 parts of methylphenylindan for fifteen minutes. The undissolved sodium sulfite is allowed to settle and the hot solution of sodium β-naphtholate in methylphenylindan at 260° C. is pumped into a stirred autoclave which has been preheated to 255° C. The autoclave is closed and at an internal temperature of 255° C. dry carbon dioxide is pressed in up to a pressure of 5 atmospheres. Carboxylation and processing are carried out analogously to Example 1. 34 parts of 2-hydroxynaphthalene-3-carboxylic acid having a melting point of 212° to 215° C. is obtained (60% of theory based on β-naphthol used up).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:17]([O:24][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl alcohol and DBU in dioxane. ES-MS m/e (%): 304 (M{37Cl}+H+, 30), 302 (M{35Cl}+H+, 100).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([C:10](=[O:21])[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[N:7]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:6]1)=O.[BH4-].[Li+].C(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[C:25]([O:24][C:22]([N:7]1[CH2:6][C@@H:5]([CH2:3][OH:2])[CH2:9][C@H:8]1[C:10](=[O:21])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[F:20])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 2 h

Procedure:
To a solution (3S,5S)-5-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (550 mg, 1.33 mmol) in THF (6 mL) was added lithium borohydride (2 M in THF, 1.46 mL, 2.92 mmol) at RT and the mixture was further stirred for 2 h under N2 atmosphere. After completion brine and CH2Cl2 were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude was purified by flash column chromatography on silica gel (eluent: EtOAc) to give the desired material. MS (LC/MS): 409.1 [M+Na]+, 287.0 [MH−Boc]+, 385.1 [M−H]−; tR (HPLC conditions f): 1.82 min.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[N:39][C:40]([NH:43][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7](=[O:23])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:41][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-[6-(8-cyclopentyl-6-ethoxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140 g, 14.7%). 1H NMR δ(400 MHz, CDCl3) 8.59 (s, 1H), 8.26 (d, J=9.3 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.6 (t, J=1.5 Hz, 1H), 7.38 (dd, J=2.7, 9.0 Hz, 1H), 5.89 (m, 1H), 4.55 (d, J=1.2 Hz, 1H), 3.66 (q, J=7.1 Hz, 2H), 3.60 (m, 4H), 3.11 (m, 4H), 2.34 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).