Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([OH:19])=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH:22]1[CH2:26][CH2:25][C:24]2([C:34]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[C:28](=[O:35])[O:27]2)[CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2([C:17]([N:22]3[CH2:26][CH2:25][C:24]4([C:34]5[CH:33]=[CH:32][N:31]=[CH:30][C:29]=5[C:28](=[O:35])[O:27]4)[CH2:23]3)=[O:19])[CH2:15][CH2:16]2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Reactant: O=C(O)C1(c2ccc(Oc3ccccc3)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(Oc5ccccc5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(4-phenoxyphenyl)cyclopropanecarboxylic acid (15 mg, 0.059 mmol), 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (16 mg, 0.059 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (27.4 mg, 0.062 mmol), and N,N-diisopropylethylamine (36 ul, 0.21 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 4 hours. The desired product then was obtained from the mixture by prep-HPLC (6.2 mg, 25%). LCMS: m/z 427.1 (M+H)+; 449.1 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23]([C:25]1[N:26]([CH2:37][CH3:38])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([N+:34]([O-])=O)=[CH:29][CH:28]=2)=[O:24])[CH3:21].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[N:26]([CH2:37][CH3:38])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH:34][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])=[CH:29][CH:28]=2)=[O:24])[CH3:21]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
4′-Trifluoromethyl-biphenyl-2-carboxylic acid (5.04 g, 18.95 mmol) and 1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (4.00 g, 17.23 mmol) were dissolved in DCM (100 mL). DIEA (8 g, 61.8 mmol) was added to the above mixture and the mixture was stirred at room temperature for 5 minutes. PyBroP (9.63 g, 20.67 mmol) was added to the above solution in one portion. The reaction mixture was stirred for another 3 hours. The precipitate was filtered off and washed with cold DCM to provide the title compound (4.59, 54.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:11][N:10]=[C:9]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:7]=[C:6]([F:8])[CH:5]=3)[N:13]=2)=[N:15][CH:16]=1
Reactant: Fc1ccc(-c2nc(-c3cc(F)cc(Br)c3)no2)nc1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccc(-c2nc(-c3cc(F)cc(-c4cccnc4)c3)no2)nc1
Yield: 17.6 %

Procedure:
A mixture of 3-(3-bromo-5-fluorophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole (80 mg, 0.236 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (80 mg, 0.49 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 40 mg, 0.0346 mmol), in a solution of ethylene glycol dimethyl ether (1.5 mL) and 2M sodium carbonate (1.5 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane, afforded 14 mg (17.7%) 5-(5-fluoro-pyrid-2-yl)-3-[3-fluoro-5-(3-pyridyl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.95 (s, 1H), 8.76 (d, 1H), 8.66 (d, 1H), 8.37 (dd, 2H), 8.25 (s, 1H), 7.95 (d, 2H), 7.43 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH2:22])=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:20](=[O:24])[C@@H:21]([CH3:23])[NH:22][C:33]4=[O:35])=[CH:17][CH:18]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c2c(C)noc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c2c(C)noc2c1
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
N1-{4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 23, 54 mg) was dissolved in 7.0 ml of ethyl acetate. Then triethylamine (0.051 ml, 0.37 mmol) was added followed by a solution of triphosgene (24.6 mg, 0.083 mmol) in 2.0 ml of ethyl acetate. After stirring for 5 minutes, DMAP (10.1 mg, 0.083 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with an aqueous solution of NaHCO3, the mixture was extracted two times with ethyl acetate and the collected organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient c-Hex/EtOAc from 100/0 to 0/100 to afford the title compound (11 mg)
Reaction SMILES: Cl.[C:2]12([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[C:2]12([C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[CH:16][CH:17]=3)[CH2:9][CH:8]3[CH2:10][CH:4]([CH2:5][CH:6]([CH2:7]3)[CH2:11]1)[CH2:3]2
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
5.28 g (20 mmol) of 4-adamantan-1-yl-phenylamine hydrochloride were placed in 100 ml of methylene chloride and treated with 3.22 g (42.0 mmol) of pyridine. A solution of 2.39 g (22.0 mmol) of ethyl chloroformate in 15 ml of methylene chloride was added dropwise to this suspension at room temperature while stirring during 15 minutes. The reaction mixture was stirred at room temperature for 2 hours. Subsequently, the mixture was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylene chloride/n-hexane. 5.6 g of ethyl 4-adamantan-1-yl-phenyl-carbamate were obtained as a white crystallizate. M.p.: 132°-134°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].I[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C(NC(C)C)(C)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: Ic1cccs1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCOC(C#Cc1cccs1)OCC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of propargylaldehyde diethyl acetal (405 mg) in diisopropylamine (8 ml) were added 2-iodothiophene (1.2 g) and copper(II) acetate monohydrate (66.4 mg). The suspension was flushed with a stream of N2. Pd(PPh3)4 (75 mg) was added, the reaction mixture was flushed with nitrogen again. The suspension was stirred for 1 h at 55° C. A precipitate was formed and it was necessary to dilute the reaction mixture with diisopropylamine (6 ml) to keep it stirring. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→17/3 (v/v)] as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:28]2[CH2:29][CH2:30][N:25]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(c1ccccc1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and N-benzoyl-4-piperidone (87 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCN to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}phenylmethanone (152 mg, 84%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.19 min, m/z 423.35 (36), 421.34 (M++H, 100). HPLC tr=4.04 min (98.05%) 1H NMR (270 MHz, CDCl3) δ 1.24-1.44 (3H, m, CH2+NH), 1.76 (1H, m, ½CH2), 1.91 (1H, m, ½CH2), 2.72 (1H, hept, CHNH), 2.96 (1H, m, ½CH2), 3.80 (2H, m, CH2NH), 4.46 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.33-7.41 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 32.26, 33.09, 40.78, 45.67, 46.29 (CH2), 53.81 (CH), 118.95, 119.63, 124.57, 126.86, 127.97, 128.54, 128.75, 129.58, 129.85, 130.58, 131.78, 136.33, 154.35, 156.38 (ArC), and 170.00 (C═O).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][C@H:13]([N:17]2[CH2:22][C:21]3[CH:23]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[CH:26][C:20]=3[N:19]=[C:18]2[NH2:34])[CH:14]([CH3:16])[CH3:15])[CH2:5][CH2:4]1)#[N:2].C[Si]([N:41]=[N+:42]=[N-:43])(C)C.C([Sn](=O)CCCC)CCC>COCCOC>[CH3:36][N:9]([CH:6]1[CH2:7][CH2:8][CH:3]([C:1]2[NH:43][N:42]=[N:41][N:2]=2)[CH2:4][CH2:5]1)[C:10](=[O:35])[CH2:11][CH2:12][C@H:13]([N:17]1[CH2:22][C:21]2[CH:23]=[C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=[CH:26][C:20]=2[N:19]=[C:18]1[NH2:34])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)[C@H](CCC(=O)N(C)C1CCC(C#N)CC1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: CC(C)[C@H](CCC(=O)N(C)C1CCC(c2nnn[nH]2)CC1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Temperature: 150 °C

Procedure:
To a solution of 4-(S)-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-5-methyl-hexanoic acid (4-cyano-cyclohexyl)-methyl-amide (0.26 g, 0.43 mmol) and trimethylsilylazide (0.17 mL, 1.29 mmol) in DME (1.5 mL) was added dibutyltin oxide (0.10 g, 0.40 mmol). The mixture was then heated in a microwave at 150° C. for 20 min. The solution was purified by HPLC to yield 4-(S)-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-5-methyl-hexanoic acid methyl-[4-(1H-tetrazol-5-yl)-cyclohexyl]-amide as a white solid, as its corresponding trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C=O.O.[C:41]([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:41])[CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: [BH3-]C#N
Reactant: CCN(c1cc(C#CC2CCNCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(c1cc(C#CC2CCN(C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(piperidin-4-ylethynyl)benzamide (100 mg, 0.198 mmol) in methanol (5 mL) was added 35% formaldehyde in H2O (0.155 mL, 1.98 mmol) at 0° C. After stirring at 0° C. for 10 min, sodium cyanoborohydride (24.9 mg, 0.396 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. LCMS indicated that the reaction was completed. The reaction was quenched with sat. NaHCO3/brine and extracted with EtAOc/Heptane. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (10 g column, MeOH/DCM=1:9, and then MeOH/7 M NH3 in MeOH/DCM=1:1:8) to afford the titled compound (96.0 mg, 93%). 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (brs, 1H), 7.08 (brs, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 3.94-3.87 (m, 2H), 3.35-3.30 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 3.04-2.97 (m, 1H), 2.79-2.71 (m, 2H), 2.67-2.58 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.28-2.21 (m, 2H), 1.97-1.91 (m, 2H), 1.78-1.67 (m, 4H), 1.64-1.54 (m, 2H), 0.85 (t, J=7.0 Hz, 3H); MS (ESI) [M+H]+519.4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC(C)(C)C)=[O:9])=[C:6]([C:15]2[CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[N:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1COCC1>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:15]2[CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[N:3]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of di(tert-butyl) 2′-amino-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1,3′(2H)-dicarboxylate (50.0 mg, 0.09 mmol) in THF (4.5 mL) was added sodium bis(2-methoxyethoxy)aluminum hydride (0.10 mL) dropwise, then stirred for 1 hr at 0° C. The reaction was quenched by an addition of saturated NH4Cl solution, filtered, and washed with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by preparative silica gel TLC (15% acetone in chloroform) to give tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate as a white foam (25 mg, yield 57%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.C(=O)(OC(C)(C)C)[O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>O.ClCCl>[NH2:20][C:17]1[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[N:19]=[C:15]([O:14][CH2:13][C:7]2[CH:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml) was added to a solution of 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolved in dichloromethane (40 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (6.8 g, 31.2 mmol) dissolved in DCM (35 ml) was added and the reaction mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was separated and the organic layer was washed with water (2×15 ml) and brine (2×15 ml), dried over sodium sulphate, filtered, evaporated and dried in vacuo to give tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g, 99%) as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH2:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:29]2)=CC=1>O1CCCC1>[NH2:19][C:17](=[S:29])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=S
Temperature: 25 °C
Yield: 130.6 %

Procedure:
To a solution of #12 (14.060 g, 53.192 mmol, 1 eq.) in tetrahydrofuran (180 mL, 0.296 M), was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent) (12.70 g, 31.40 mmol, 0.59 eq.) and the reaction was refluxed for 90 minutes. The reaction was cooled to room temperature and quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate, concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), affording #13 (11.50 g, 77%) as a white solid. LC-MS: m/z 279.4 [M−H+], 225.2 [(M−2-methylprop-1-ene)+H+], 181.2 [(M−Boc)+H+]; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 9.60 (br s, 1H), 9.19 (br s, 1H), 7.23-7.32 (m, 5H), 6.82 (d, J=8.8 Hz, 1H), 4.44 (ddd, J=9.4, 9.1, 4.4 Hz, 1H), 3.00 (dd, J=13.7, 4.5 Hz, 1H), 2.79 (dd, J=13.6, 9.9 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)C.[H][H]>[OH-].[OH-].[Pd+2].C(N(CC)CC)C>[NH2:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [H][H]
Reactant: CC(C)Cn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
1.0 gram of 4-(N-benzylamino)-1-isobutyl-1H-imidazo(4,5-c)quinoline is added to 10 mL of ethanol, followed by the addition of 0.03 gram triethylamine and 0.2 gram of Pearlman's catalyst (20% Pd(OH)2/C). The mixture is stirred at 40° C. under 1 atm hydrogen until completion. The mixture is then filtered through Celite® and the filtrate, containing 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline (imiquimod), is concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([NH:18][CH2:17][CH2:16][NH2:19])=[S:14])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCCN
Reactant: Cc1c(N=C=S)cc(F)c2cccnc12
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(F)c2cccnc12
Reaction time: 0.17 h

Procedure:
N-(5-Fluoro-8-methyl-7-quinolinyl/-N'-2-aminoethylthiourea. A solution of 5-fluoro-8-methyl-7-quinolinylisothiocyanate (0.38 g) in toluene (40 mL) is added dropwise to a solution of 1,2-ethylenediamine (0.78 g) in toluene (40 mL). A white precipitate is observed after the reaction stirs for 10 minutes at room temperature. The precipitate is filtered and dried in vacuo to afford N-(5-fluoro-8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:35])[C:18]([OH:34])([C:23]3[CH:33]=[CH:32][C:26]4[N:27]([CH3:31])[C:28](=[O:30])[O:29][C:25]=4[CH:24]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:36])[CH:12]=2)=[CH:7][C:6]=1[F:37])=[O:4].[Li+].[OH-].O>C1COCC1>[Cl:36][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:37])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:35])[C:18]([OH:34])([C:23]1[CH:33]=[CH:32][C:26]2[N:27]([CH3:31])[C:28](=[O:30])[O:29][C:25]=2[CH:24]=1)[C:19]([F:22])([F:20])[F:21]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Temperature: 25 °C
Yield: 22.2 %

Procedure:
3′-Chloro-3-fluoro-4′-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propyl]-biphenyl-4-carboxylic acid methyl ester (60 mg, obtained in Example 134, step 1) was dissolved in THF (4 mL) followed by the addition of aqueous LiOH solution (1.0M, 0.145 mL). The mixture was stirred over night at r.t. The reaction mixture was poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl to pH 1 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=7:3 to 1:1) to give the title compound as a brown solid (13 mg, 22%). MS (neg. ion, m/e)=522.2 [(M−H)−].
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:38]C=2C=1.N.C(Cl)CCl.C(N1CCOCC1)C.CCN=C=NCCCN(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH2:38])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(N)=O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A flask was charged with 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see example 6) (109 mg, 0.251 mmol), HOBT.NH3 (85 mg, 0.501 mmol) and EDC (57.7 mg, 0.301 mmol) then filled with dichloromethane (DCM) (5 mL) and the resulting mixture was treated with N-ethylmorpholine (NEM) (0.095 mL, 0.752 mmol) then stirred a room temperature. After 4 h, 50% of the previous quantities of EDAC, HOBT and NEM were added and the resulting mixture was stirred at room temperature for 16 h. Most of the DCM was removed in vacuo and the residue was partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed twice with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O then filtered off and dried under house vacuum to give 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzamide (75 mg, 0.173 mmol, 69.0% yield) as a very pale yellow solid.