Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:23]([O-])=O)=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:8]([F:13])=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([F:13])=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:6]=1[NH2:23])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(OC)c(F)c(Nc2ccc(I)cc2F)c1N
Temperature: 70 °C
Yield: 96.3 %

Procedure:
To a solution of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (Intermediate 7, 1.0 g, 2.22 mmol) in THF (8 mL) was drop wise added NaOMe solution [prepared by dissolving Na metal (51 mg, 2.2 mmol) in methanol (5 mL)] at −78° C. After complete addition, the reaction mixture was warmed to room temperature and stirred for 16 h. The progress of reaction was monitored by TLC. After completion, reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with water (20 mL×2), dried over anhydrous sodium sulfate and concentrated to yield 3-allyloxy-6-fluoro-5-methoxy-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (820 mg). A suspension of (3-allyloxy-6-fluoro-5-methoxy-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (800 mg, 1.73 mmol) in ethanol (10 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, a freshly prepared solution of Na2S2O4 (900 mg, 5.2 mmol) in water (1.8 mL) was added drop wise and stirred the reaction mixture at 90° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to yield 6-allyloxy-3-fluoro-N2-(2-fluoro-4-iodo-phenyl)-4-methoxy-benzene-1,2-diamine (720 mg). 1H-NMR (400 MHz, CDCl3): δ3.74 (2H, bs), 3.83 (3H, s), 4.56 (2H, d, J=5.6), 5.32 (1H, d, J=10.8), 5.40-5.45 (2H, m), 6.04-6.09 (1H, m), 6.24 (1H, t), 6.52 (1H, d, J=7.6), 7.21 (1H, d, J=8.4), 7.36 (1H, d, J=10.4).
Reaction SMILES: Br[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C[Si]([C:21]#[N:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl.O>C(Cl)Cl>[Cl:15][CH2:14][CH2:13][CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:4])([CH3:3])[C:21]#[N:22])=[CH:10][CH:9]=1)=[O:16]
Reactant: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1ccc(C(=O)CCCCl)cc1

Procedure:
Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.00 g, 6.59 mmol) in anhydrous methylene chloride (20 mL) and place under an argon atmosphere. Add trimethylsilyl cyanide (1.10 mL, 8.25 mmol) followed by tin (IV) chloride (0.20 mL, 1.7 mmol) via syringe. Stir at reflux for 1 hour, add water (20 mL) and stir for an additional ½ hour. Separate the layers and extract the aqueous layer with methylene chloride. Combine the organic layers, wash with brine, dry (MgSO4), filter and evaporate the solvent in vacuo. Purify by silica gel chromatography (15% ethyl acetate/hexane) to give the title compound as a white solid; mp 79-80° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=3)=[CH:17][CH:16]=2)[C:10]2[N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2].[OH-].[K+]>CO>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:31]=3)=[CH:19][CH:20]=2)[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCCN2C(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCCN2
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A solution of compound B5 (0.42 g) and potassium hydroxide (0.1 g) in methanol (5 ml) was left to stand for 1 hour. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was separated, washed with saturated sodium chloride solution (20 ml) and dried (MgSO4) The solvent was removed by evaporation and ether (10 ml) was added to the residue. Insoluble material was removed by filtration and the filtrate was evaporated to give 2-ethyl 5,6,7,8-tetrahydro-4-(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl)-4-yl)methoxy]-1,5-naphthyridine (A5) (0.12 g), as a foam; NMR (d6 -DMSO): 1.15(t,3H), 1.8-1.9(m,2H), 2.5(q,2H), 2.7(t,2H), 3.05-3.15(m,2H), 5.05(s,2H), 6.65(s,1H), 6.8-6.9(m,6H), 7.1(d,2H), 7.2-7.7(complex m,14H), 7.9(dd,1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1>C(O)(C)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=[C:2]2[O:13][CH:8]([CH3:9])[CH3:7])=[CH:7][C:8]=1[OH:13]
Reactant: Cc1cc(Nc2cc3cc(O)c(F)cc3c(Br)n2)n[nH]1
Solvent: CC(C)O
Product: Cc1cc(Nc2cc3cc(O)c(F)cc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 376 was used, starting from 1-Bromo-7-fluoro-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol, isopropanol, to give 7-Fluoro-1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol. LC-MS: m/e 317 (MH+).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:44]1[C:45]2[C@H:52]([CH3:53])[CH2:51][CH2:50][C:46]=2[N:47]=[CH:48][N:49]=1.[Cl:54][C:55]1[CH:56]=[C:57]2[C:63]3([CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]3)[CH2:62][NH:61][C:58]2=[CH:59][CH:60]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[Cl:54][C:55]1[CH:56]=[C:57]2[C:63]3([CH2:64][CH2:65][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:67][CH2:68]3)[CH2:62][N:61]([C:44]3[C:45]4[C@H:52]([CH3:53])[CH2:51][CH2:50][C:46]=4[N:47]=[CH:48][N:49]=3)[C:58]2=[CH:59][CH:60]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Cl)cc12
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A pear-shaped flask was charged with Pd(OAc)2 (2.1 mg, 0.0093 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (8.1 mg, 0.014 mmol) and purged with nitrogen. To the flask was added (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (19 mg, 0.11 mmol), tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate (30 mg, 0.093 mmol), Cs2CO3 (45 mg, 0.14 mmol) and toluene (0.9 mL). The mixture was heated at about 100° C. for 4 hours. After cooling to about room temperature, the reaction was diluted with EtOAc, filtered through CELITE® (Celite Corp., Santa Barbara, Calif.), and concentrated. The crude product was purified by column chromatography (hexanes:EtOAc, 5:1 to 3:1) to give (R)-tert-butyl 5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate as an oil (30 mg, 71%). LCMS (APCI+) m/z 455, 457 [M+H]+; Rt=4.14 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-])=O.CC(O)=O>C1COCC1.[Zn]>[S:11]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[N:9]=[CH:10]1
Reactant: O=[N+]([O-])c1ccc2scnc2c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitrobenzo[d]thiazole (150 mg) was dissolved in THF (20 mL) at 0° C. and AcOH (1 mL) was added followed by Zinc dust (1.65 g). Mixture was stirred at RT for 1 h and was filtered on silica pad (rinsed with EtOAc). Solvent was evaporated, residue was diluted with NaHCO3 and extracted with EtOAc. Organic phases was dried, filtered and evaporated to give benzo[d]thiazol-5-amine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].Cl>[OH-].[K+].O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1

Procedure:
60 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde were dissolved in 500 ml of 0.1N methanolic potassium hydroxide solution and the solution was treated portionwise within 1 hour at 0° C. with 3.1 g of sodium borohydride. Thereafter, the reaction mixture was diluted with about 200 ml of water and cautiously adjusted to pH 2-3 in an ice-bath with about 40 ml of 25 percent hydrochloric acid. The mixture was extracted with methylene chloride and the organic phase was dried over magnesium sulphate and concentrated. Crystallization from a mixture of 250 ml of ethyl acetate and 250 ml of petroleum ether gave 45.75 g of trans-4-(p-cyanophenyl)-hydroxymethylcyclohexane (purity 99.6%) as colourless crystals with m.p. 108° C.
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH2:23][CH2:22]3)=[O:20])=[C:10]2[CH2:9]1)=O)(C)(C)C.[ClH:37]>CO>[ClH:37].[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]1[CH2:25][CH2:26][N:21]([C:19]([C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]3[CH2:35][CH2:36][NH:8][CH2:9][C:10]=23)=[O:20])[CH2:22][CH2:23]1
Reactant: COc1ccccc1C1CCN(C(=O)c2c3n(c4ccccc24)CCN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Solvent: CO
Product: COc1ccccc1C1CCN(C(=O)c2c3n(c4ccccc24)CCNC3)CC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A mixture of 0.085 g (0.17 mmol) 10-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester and 1.4 ml of a 1.25 M solution of hydrochloric acid (1.7 mmol) in methanol was stirred for 15 min at 50° C. The reaction mixture was concentrated in vacuo to give the title compound (0.072 g, 97%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([NH:15][C:16](=O)[O:17]CC)=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4].C[O-].[Na+].[NH2:26]/[C:27](/[C:34]([F:37])([F:36])[F:35])=[CH:28]\[C:29]([O:31]CC)=O.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:29](=[O:31])[CH:28]=[C:27]([C:34]([F:35])([F:36])[F:37])[NH:26][C:16]3=[O:17])=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)OC)oc12
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Yield: 59.3 %

Procedure:
An additional 0.6 gram of 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione was prepared in the manner of Step E, Example 1, with 0.8 gram (2.4 mmole) of ethyl N-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl]carbamate, 0.15 gram (2.8 mmole) of sodium methoxide, 0.44 gram (2.4 mmole) of ethyl 3-amino-4,4,4-trifluorocrotonate, 30 mL of N,N-dimethylformamide, arid 0.37 gram (2.4 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene as reagents. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[Cl-].[CH:32]1([Zn+])[CH2:34][CH2:33]1>C(Cl)Cl.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>[CH:32]1([C:2]2[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]3[NH:6][C:7]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=5)[CH:15]=4)=[N:8][C:9]=3[N:10]=2)[CH2:34][CH2:33]1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CCCn1c(C2CC2)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 100 °C
Yield: 23 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (prepared using same procedure as given in Example 2) (0.1 g, 0.23 mmol), Pd(PPh3)4 (0.319 g, 0.28 mmol) and cyclopropyl zinc chloride solution (10 ml, 0.5 M solution) were heated at 100° C. for 30 minutes. Reaction mixture was cooled, diluted with DCM (10 ml). Organic layer washed with brine (2×10 ml), dried over Na2SO4, evaporated and purified by preparative TLC to obtain pure 2-Cyclopropyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as white solid (23 mg, 23%)
Reaction SMILES: [CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][CH:33]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:11][CH2:12][N:13]([CH2:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C1c2ccccc2OC2(CCNCC2)CN1Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2OC2(CCN(CCCc3ccccc3)CC2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 30 (0.01 mmol) in tetrahydrofuran (0.4 mL) were added 3-phenylpropanal (0.02 mmol) and MP-BH(OAc)3 (Argonaut, product number 800415, loading; 2.25 mmol/g) (13.3 mg). The mixture was stirred overnight at 25° C. To the reaction mixture were added tetrahydrofuran (0.4 mL) and PS-NHNH2 (Argonaut, product number 800272, loading; 3.65 mmol/g) (8.2 mg). After stirring overnight, the mixture was filtered and the filtrate was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[OH:51][CH2:52][C@@H]1NC[C@@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[C@@H:27]([CH2:52][OH:51])[CH2:26][C@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OC[C@H]1C[C@H](O)CN1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2C[C@@H](O)C[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3S,5R)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride and isolated as white solid. MS (m/e): 417.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[NH:8][N:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:6]1[C:5]2[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:10][C:9]=2[NH:8][N:7]=1
Reactant: CC1(C)CCc2cn[nH]c2C1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)CCc2c(I)n[nH]c2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
To a solution of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (0.50 g, 3.33 mmol) in DMF (8 mL) at room temperature was added powdered potassium hydroxide (560 mg, 10.0 mmol) and iodine (1.69 g, 6.66 mmol). The maroon reaction mixture was stirred at room temperature for 45 min then quenched with 10% aqueous Na2S2O3, diluted with water and extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated to afford 920 mg (99%) of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole as a light yellow waxy solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.44 (s, 2H), 2.35 (t, J=6.4 Hz, 2H), 1.55 (t, J=6.4 Hz, 2H), 1.01 (s, 6H).
Reaction SMILES: Br.[Cl:2][C:3]1[C:12]([OH:13])=[C:11]([OH:14])[C:10]([Cl:15])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[N:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:2][C:3]1[C:12]([OH:13])=[C:11]([OH:14])[C:10]([Cl:15])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:25](=[O:26])/[CH:24]=[CH:23]/[C:22]1[C:17]([CH3:16])=[N:18][C:19]([C:28]([F:29])([F:30])[F:31])=[CH:20][CH:21]=1)[CH2:8]2
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Reactant: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.9 %

Procedure:
5,8-Dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydro bromide (183 mg, 0.58 mmol), (E)-3-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acrylic acid (140 mg, 0.64 mmol), EDC.HCl (167 mg, 0.87 mmol), HOBt (89 mg, 0.58 mmol), DMAP (147 mg, 1.2 mmol) and Cs2CO3 (391 mg, 1.2 mmol) were suspended in DMF (15 mL) and stirred at rt for 12 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Combined organics were washed with NaHCO3 (2×30 mL, sat. aq.), water (3×30 mL) and brine and dried (MgSO4). After filtration and evaporation the residue was purified by column chromatography (SiO2, CH2Cl2:MeOH 95:5) and was then further purified by size exclusion chromatography (sephadex, CHCl3:MeOH 1:1) to give the title compound (28 mg, 63 μmol, 11%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[C:27]([F:26])([F:36])[F:37])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCCCCCCCCCCCOc1ccc(C=O)c2ccccc12
Product: CCCCCCCCCCCCOc1ccc(CNCc2ccccc2C(F)(F)F)c2ccccc12

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(dodecyloxy)-1-naphthaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. HPLC (Condition A), Rt: 5.54 min (HPLC purity: 98.0%).
Reaction SMILES: C(O[C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)[C:31]1[C:32]([O:37][CH3:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>FC(F)(F)C(O)=O>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)CN(CC(=O)N1CCC[C@H]1C#N)C(=O)OC(C)(C)C
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)N(CC(=O)N1CCC[C@H]1C#N)CC(C)C
Temperature: 0 °C
Yield: 64.2 %

Procedure:
(2S)-1-(2-(N-tert-Butyloxycarbonyl-N-(2-methylpropyl)amino)acetyl)pyrrolidine-2-carbonitrile (25 mg, 0.081 mmol) was treated with trifluoroacetic acid (50 ml). After 1 h at room temperature the solvent was removed in vacuo and the residue dissolved in CH2Cl2 (100 ml). The solution was cooled to 0° C., triethylamine (30 mg, 0.3 mmol) was added followed by 2-anisoyl chloride (15 mg, 0.088 mmol). After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue dissolved in ethyl acetate (200 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 2% methanol, 98% chloroform) to give a colourless oil identified as the title compound (18 mg, 0.052 mmol, 66%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH2:11][CH2:10][CH2:9][CH2:8]3.C(O)(=[O:16])C>C(O)(=O)CC>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH2:11][CH2:10][CH2:9][C:8]3=[O:16]
Reactant: c1c2c(cc3c1CCO3)CCCC2
Reactant: CC(=O)O
Solvent: CCC(=O)O
Product: O=C1CCCc2cc3c(cc21)CCO3
Temperature: 5 °C

Procedure:
30 g of the compound of Example 16 are dissolved in 130 ml of acetic acid and 32 ml of propionic acid, and then cooled to between 0° and 5° C. A solution of Jones's reagent is added, the temperature being maintained at approximately 5° C. The mixture, maintained for one hour at this temperature, is concentrated under vacuum and then taken up with sodium bicarbonate solution in the presence of ether. After filtration, the ether phase is decanted and washed with saturated sodium chloride solution to obtain, after evaporation and drying, an oil which crystallizes.
Reaction SMILES: [Si:1]([O:8][C:9]1([CH2:12][CH:13]=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](O)(CC)(CC)CC.[CH3:23][C:24]([S@:27]([NH2:29])=[O:28])([CH3:26])[CH3:25]>C(Cl)Cl>[Si:1]([O:8][C:9]1([CH2:12]/[CH:13]=[N:29]/[S@@:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OC1(CC=O)CC1
Agent: CC[Si](O)(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/CC1(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
To a 1.0 L round bottom flask containing 2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)acetaldehyde (5.00 g, 23.3 mmol) (crude 10.5 g with TESOH, 1H NMR showed about 50/50 sm to impurity) was added DCM (200 mL) and the mixture was allowed to stir at 23° C. for 5 min. At this time, (R)-2-methylpropane-2-sulfinamide (2.83 g, 23.3 mmol) and cupric sulfate anhydrous (2.58 ml, 58.3 mmol) were added and the reaction was allowed to stir for 40 h. The copper salts were removed by celite filtration. The filtrate was concentrated to give a yellow oil that was purified on a 330 g Isco column (5 to 20% EtOAc in hexanes) to afford the title compound as a colorless oil.