Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>>[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH:42][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(NCCN(C)C)cn3)C4)n[nH]c2c1
Yield: 45.5 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 193 μmol) and N,N-dimethylethylendiamine, (34 mg, 386 μmol) using the method of Example 32. The crude material was purified by HPLC Method E to afford (50 mg, 46%) of the title compound as white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9](Br)=[CH:8]2)(=O)C.[NH:16]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([N:16]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]1)=[CH:8]2
Reactant: CC(=O)Oc1ccc2ncc(Br)cc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cnc3ccc(O)cc3c2)C1
Temperature: 110 °C
Yield: 12 %

Procedure:
A mixture of Intermediate A (1.50 g, 5.07 mmol), tert-butyl pyrrolidin-3-ylcarbamate (1.13 g, 6.09 mmol), Pd2(dba)3 (0.232 g, 0.254 mmol), Xantphos (0.294 g, 0.507 mmol) and KOtBu (1.14 g, 10.2 mmol) in DMF (15 mL) was bubbled with argon for 20 min. The result mixture was heated at 110° C. overnight. The solution was cooled to rt and the solvent was removed under reduced pressure. The residue was diluted with water, extracted with DCM three times. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography (eluting with 5% MeOH in DCM) to give the title compound as yellow solid (0.2 g, yield 11%). LCMS (method N): [M+H]+=330, tR=1.93 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4](=[O:11])[CH:5]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:7]([CH3:9])([CH3:10])[CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC1=CC(C)(C)CCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 2-methoxy-4,4-dimethyl-cyclohex-2-enone (12.5 g, 81.1 mmol) and diethyl oxalate (12.1 mL, 89.2 mmol) in ethyl ether was treated with a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran under argon atmosphere. The reaction was stirred at room temperature for 2 hours, poured into a 10% NaH2PO4 solution (500 mL) and extracted with diethyl ether (300 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was taken up with hexane, stirred and filtered to give the title compound (16.8 g, 81.5% yield) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:16](Cl)=[CH:15][C:12]([NH:13][CH3:14])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[C:16]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:15][C:12]([NH:13][CH3:14])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1
Reactant: CN1CCNCC1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(N2CCN(C)CC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from N-methylpiperazine (200 mg, 2.0 mmol), 4,5-dichloro-N-methyl-2-nitroaniline (442 mg, 2.0 mmol) and potassium carbonate (304 mg, 2.2 mmol) in DMF (10 mL) in accordance to example 9 step (d).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:40][C:41]([CH3:54])([CH3:53])[C@@H:42]([NH:49][C:50]([NH2:52])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[OH:40][C:41]([CH3:54])([CH3:53])[C@@H:42]([NH:49][C:50]([NH:52][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Reactant: CC(C)(O)[C@@H](NC(N)=O)c1ccccc1
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@@H](c3ccccc3)C(C)(C)O)nc(CO)c12
Temperature: 95 °C
Yield: 77.4 %

Procedure:
(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 500 mg, 1.097 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(ii) (88 mg, 0.110 mmol), cesium carbonate (893 mg, 2.74 mmol) and (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)urea (21B, 343 mg, 1.645 mmol) were taken up in an oven dried 2 mL round bottom flask equipped with magnetic stir bar and degassed 3× under nitrogen. Anhydrous dioxane (8 ml) was added the reaction was degassed 3× under nitrogen and heated to 95° C. for 14 hours. The crude reaction mixture was diluted with 2 mL DCM and filtered a syringe filter. The filtrate was concentrated in vacuo and the residue was purified on silica gel, 5-50% EtOAc/DCM to provide (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (533 mg, 0.849 mmol, 77% yield). MS: [M+H]+ m/z 628.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[F:33][C:34]([F:50])([F:49])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1>CN(C=O)C>[F:49][C:34]([F:33])([F:50])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=2[NH2:1])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
2-amino-3-hydroxybenzoic acid (1 g, 6.5 mmol) was dissolved in 20 ml of DMF and at 0° C. EDCI (1.4 g, 1.2 equiv.), hydroxybenzotriazole (1 g, 1.2 equiv.) and amine 2c (2 g, 1.2 equiv.) were added. The mixture was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from EtOAc/ether gave 1.6 g of a beige solid. Yield=62.5% [M+1] 393.4 (C20H22F3N3O2 requires 393.4).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:47])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[Cl:45])=[O:35])[CH2:16][C@@H:17]([OH:32])[CH2:18][O:19][P:20]([O:27]C(C)(C)C)([O:22]C(C)(C)C)=[O:21])[N:2]=1.Cl>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:47])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[Cl:45])=[O:35])[CH2:16][C@@H:17]([OH:32])[CH2:18][O:19][P:20]([OH:27])([OH:22])=[O:21])[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(O)O
Reaction time: 0.5 h

Procedure:
To a solution of the above crude (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(di-tert-butoxyphosphoryloxy)-4-hydroxypentyl isoquinolin-3-ylcarbamate in MeOH (8 mL) at 0° C. was added conc. HCl (12 N, 8 mL, 20 equiv.) dropwise. The mixture was stirred for 30 min and concentrated. The residue was dissolved in 50 mL H2O. Aqueous NaOH solution (1 N) was added to adjusted the PH to 3˜4. EtOAc (50 mL) was then added. The mixture was stirred at RT for 1 h. The white solid was then filtered and washed with H2O and EtOAc, followed by drying in vacuo to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate as a white powder (2.4 g, 86% for 2 steps). LRMS (M+H) m/z 585.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.ClC1C(C(O)=O)=C(C(=O)C2C=CC(Cl)=CC=2)C=CC=1.Cl.[N+:40]([C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1)([O-:42])=[O:41]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:19])[N:48]([CH2:47][C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:50][CH:49]=1)[C:5]2=[O:7]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1cccc(Cl)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(c1ccc(Cl)cc1)c1cccc(Cl)c1C(=O)O
Product: O=C1c2cccc(Cl)c2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
The named compound was synthesised from a mixture of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid (2.15 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10%-20% EtOAc/petrol) and obtained as a white solid (1.96 g, 63%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:18][OH:19]>>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CCCN2CCCCC2)CC1
Agent: Cl
Product: ON=C1CCN(CCCN2CCCCC2)CC1

Procedure:
1-(3-(1-Piperidinyl)propyl)-4-piperidone oxime is prepared from 1-(3-(1-piperidinyl)propyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:16]=[N:17][CH:18]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2cncc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4,5-trifluorobenzaldehyde and 5-chloropyridin-3-ol.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([C:13]([N:15]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=O)(C)C.C[O-].[Na+]>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:18]2[C:17](=[O:30])[C:16]3[N:15]([C:13](=[O:14])[C:12]4[CH:11]=[CH:10][CH:9]=[N:8][C:7]=4[C:5]=3[OH:4])[CH2:20][C:19]2=[O:21])=[CH:24][CH:25]=1
Reactant: CC(C)OC(=O)c1ncccc1C(=O)N1CC(=O)N(Cc2ccc(F)cc2)C(=O)C1
Agent: C[O-]
Agent: [Na+]
Product: O=C1Cn2c(c(O)c3ncccc3c2=O)C(=O)N1Cc1ccc(F)cc1

Procedure:
A solution of 31 (5 mg, 0.01 mmol) in 0.3 mL of dry 0.5 M NaOMe was stirred at ambient temperature for 15 minutes when a yellow precipitate formed. The solvent was removed in vacuo and the solid was dissolved in a mixture of CH2Cl2— 1N HCl. The layers were separated and the aqueous layer was washed with CH2Cl2. The organic solvent was removed to provide an off-white solid. The product 32 was purified by trituration using CH2Cl2 and hexane. 1H NMR (300 MHz, CDCl3) δ 5.01 (s, 2H), 5.16 (s, 2H), 7.02 (dt, 2H, J=2, 9 Hz), 7.51 (ddd, 2H, J=2, 5, 9 Hz), 7.79 (dd, 1H, J=8, 5 Hz), 8.61 (dd, 1H, J=8, 2 Hz), 9.13 (dd, 1H, J=4, 2 Hz), 12.35 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 42.4, 46.1 107.0, 115.5, 115.8, 126.7, 127.1, 130.8, 131.4, 131.5, 132.5, 143.2, 148.4, 153.7, 156.0, 162.2 (d, J=249 Hz), 163.9, 164.0; EI MS (m/z) 354.6 [MH+].
Reaction SMILES: NC1C=CC(NC(N)=S)=CC=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[NH:23][C:24]([NH2:26])=[S:25]>>[NH2:26][C:24]1[S:25][C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[CH:22][C:13]=3[NH2:12])[C:18]=2[N:23]=1
Reactant: NC(=S)Nc1cccc2c(N)cccc12
Agent: NC(=S)Nc1ccc(N)cc1
Product: Nc1nc2c(ccc3c(N)cccc32)s1

Procedure:
When the reaction is carried out as described in Example 4, but instead of 4-aminophenylthiourea an equimolar amount of 5-amino-1-naphthylthiourea is used, 2,6-diaminonaphtho[1,2-d]thiazole is obtained in an equally good yield and quality.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.[NH2:23][C:24]1[N:29]=[C:28]([OH:30])[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][C:33]=2[O:40][CH3:41])=[C:26]([CH3:42])[N:25]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:30][C:28]1[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][C:33]=2[O:40][CH3:41])=[C:26]([CH3:42])[N:25]=[C:24]([NH2:23])[N:29]=1)(=[O:11])=[O:10]
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 84.8 %

Procedure:
2-Mesitylenesulfonyl chloride (7.2 g) was added to a suspension of diisopropylethylamine (5.5 mL) and the product from step (iii) (6.1 g) in THF (200 mL) and the mixture was stirred under reflux for 12 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (8.6 g) as a white solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.86 (1H, s), 6.77 (2H, s), 4.67 (2H, br s), 4.64 (2H, d), 3.82 (3H, s), 3.81 (2H, s), 2.57 (6H, s), 2.29 (3H, s), 2.21 (3H, s), 1.81 (1H, t).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9]1.C(O)(=O)C.[NH4+:27].[Cl-:28]>CO>[Cl-:28].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH2:27])=[NH2+:18])=[N:9]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ccccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=[NH2+])c1nn(Cc2ccccc2F)c2ccccc12
Temperature: 40 °C
Reaction time: 22 h

Procedure:
A sodium methoxide solution, which had been prepared from 190 mg (8.26 mmol) of NaOMe and 30 ml of abs. methanol, was added to a solution of 20.0 g (97.7 mmol) of 1-(2-fluorobenzyl)-3-cyanoindazole (from Example IX) in 200 ml of methanol, and the mixture was stirred at 40° C. for 22 h. After addition of 0.46 ml of acetic acid and 4.30 g of NH4Cl, the mixture was stirred at 40° C. for another 24 h and subsequently concentrated to dryness using a rotary evaporator. The residue was taken up in acetone and the remaining precipitate was filtered off with suction, giving, after drying under high vacuum, the product in the form of a light-beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH:23]=2)=[CH:8][C:9]=1[N:10]([C:37]([C@H:34]1[CH2:35][CH2:36][C@H:31]([CH3:30])[CH2:32][CH2:33]1)=[O:38])[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1NC1CCC(n2cncn2)CC1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1

Procedure:
5-(4,4-Dimethyl-cyclohex-1-enyl)-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino) thiophene-2-carboxylic acid methyl ester (0.800 g, 2 mmol) was acylated with trans-4-methylcyclohexyl carboxylic acid chloride as previously described (example 1, step II) to give 5-(4,4-Dimethyl-cyclohex-1-enyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.640 g, 60%).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]1[F:22])C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:27]([O:26][C:24]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[F:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC1CCNCC1F)OCc1ccccc1
Reaction time: 4 h
Yield: 97.9 %

Procedure:
cis-(+)-4-Benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine [(3e); Enantiomer 1] (15.0 g, 0.049 mole) in ethanol (300 ml) was hydrogenated over 20% palladium hydroxide on carbon (4g) at 30 psi for 5 h, then filtered through Celite® and evaporated. The crude amine was dissolved in ethyl acetate (100 mL), saturated sodium hydrogen carbonate solution (100 mL) was added followed by benzyl chloroformate (7.6 mL, 0.53 mole)and the mixture stirred vigorously for 4 h. The organic phase was separated dried and evaporated. The product was dissolved in DCM (75 mL) and stirred with TFA (20 mL) for 4 h then evaporated. The residue was basified with sodium carbonate solution, extracted with 10% methanol in DCM and the extracts dried and evaporated to give a white solid (12.1 g, 98%), [α]D+61.1° (MeOH).
Reaction SMILES: [O:1]([CH2:8][C:9]#[CH:10])[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1.[Li]CCCC.C=O.[C:18](Cl)(Cl)(Cl)[Cl:19]>C1COCC1>[O:1]([CH2:8][C:9]#[C:10][CH2:18][Cl:19])[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1
Reactant: C#CCOC1CCCCO1
Reactant: ClC(Cl)(Cl)Cl
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCC#CCOC1CCCCO1
Yield: 85 %

Procedure:
THPO-CH2C≡CH was treated with 1.1 equivalents of n-BuLi in THF at -78° C. for 0.5 hours and then 1.4 equivalents of paraformaldehyde ((CH2O)n) Over the course of 12 hours, the reaction was allowed to rise to 25° C. and a product isolated in 84% yield. This product was then treated with 1.6 equivalents of P(oct)3 in CCl4 at 25° C. for six hours, yielding THPO-CH2C≡CCH2Cl in 85% yield. This compound was then treated with 1.0 equivalents NA2S.9H2O in EtOH:H2O (10:1) at 25° C. for 12 hours. The product, which was isolated in 47% yield, was then treated with acetic acid (AcOH):H2O:THF (7:3:10) at 25° C. for 12 hours. The resulting product, which was isolated in 64% yield, was then treated with 3.0 equivalents of mCPBA in methylene chloride for 2 hours yielding a compound having structure (2) (R3 =R5 =H, R2 =R4 =CH2OH) in 40% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:28][CH2:27][N:26](CC4C=CC=CC=4)[CH2:25][C:14]=3[N:15]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:28][CH2:27][NH:26][CH2:25][C:14]=3[N:15]=[C:16]([CH2:18][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCNC3)cc1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A catalytic amount palladium hydroxide on carbon powder (20% Pd moisture ea. 60%) was added to a solution of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine (240 mg, 0.51 mmol) in methanol and was stirred under a hydrogen filled balloon over night at room temperature. Reaction solution was filtered through celite and filtrate was concentrated to yield the product as a white powder (150 mg).
Reaction SMILES: [BH4-].[Na+].C(C(CCCC)C(O)=O)C.[F:13][CH:14]1[C:19](O)(O)[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-]>ClCCCl.O>[CH2:29]([NH:36][CH:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15][CH:14]1[F:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(O)C(F)C1
Reactant: NCc1ccccc1
Agent: CCCCC(CC)C(=O)O
Agent: [BH4-]
Agent: [H-]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.2 %

Procedure:
To a slurry of NaBH4 (7.567 g, 200.0 mmol) in DCE (200 mL) was added 2-Ethylhexanoic acid (95.50 mL, 600.0 mmol) slowly over 30 minutes via addition funnel. The mixture was stirred at ambient temperature for 4 hours with venting to release H2. In a separate 1 L flask was added the product from Step B (23.53 g, 100 mmol), benzylamine (16.37 mL, 150.0 mmol) and DCE (400 mL). The hydride solution was then added via addition funnel to the mixture over 1 hours while cooling the reaction in a water bath. The reaction was stirred at ambient temperature for 2 days, then diluted with water (100 mL) and concentrated in vacuo to remove solvent. The residue was partitioned between EtOAc (300 mL) and a saturated aqueous Na2CO3 solution (2×75 mL). The mixture was shaken, the layers separated and the organic phase washed again with a saturated aqueous Na2CO3 solution (100 mL) and finally with brine (50 mL). The aqueous phases were extracted with CHCl3 (3×75 mL), and the organic phases were dried over Na2CO3, filtered and concentrated. The crude product was purified by column chromatography (EtOAc/Hexane) providing 19.55 g of the pure cis product and 5.0 g of a cis/trans mixture (80%).