Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[CH:6]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of N1-[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-D-alaninamide (Intermediate 32, 229 mg) and triethylamine (442 mg, 4.38 mmol) in dichloromethane (20 mL) was added a solution of triphosgene (216 mg, 0.73 mmol) in dichloromethane (10 mL) dropwise at 0° C. during 5 minutes. The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off and the residue was partitioned between dichloromethane (3 times 50 mL) and water (50 mL). The combined organic layers were washed with brine (3 times 10 mL), dried over sodium sulphate, filtered and concentrated to afford a grey solid, which was purified by silica gel chromatography (PE:EtOAc=2:1) to afford the title compound as a white solid (120 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].BrC1C=CC2C3N(CCCOC(C)C)C(COCC)=NC=3C(N)=NC=2C=1.N1CCCC1=O>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: O=C1NCCO1
Agent: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: O=C1CCCN1
Product: CCOCc1nc2c(N)nc3cc(N4CCOC4=O)ccc3c2n1CC(C)(C)O

Procedure:
The general method described in Part E of Example 1 was followed using 1-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and 2-oxazolidinone as reactants in lieu of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-pyrrolidinone. The product, 3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxazolidin-2-one, was isolated as a flocculent white solid, mp >250° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([NH2:30])[CH3:29]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:30][CH:28]([CH3:29])[CH3:27])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), propan-2-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 283 (M+, 6), 268 (8), 77 (7), 72 (bp), 56 (6).
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(OC(=O)C)(=[O:21])C>>[N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:21])[CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2cn3ccccc3n2)cc1
Product: O=c1cc(OCc2cn3ccccc3n2)cc[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide (1.50 g, 6.25 mmol) was heated at 140° C. in acetic anhydride (18 mL) for 2 h. The mixture was concentrated and heated at 80° C. for 2 h in 1:1 MeOH/H2O (50 mL). The resulting black solution was concentrated. The material was then partially dissolved in iPrOH (20 mL). Et2O (70 mL) was added, and the mixture was allowed to sit at ambient temperature for 1 h. The resulting solids were collected by filtration and washed with Et2O to yield the title compound (951 mg, 63%) as a dark brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.08 (br s, 1H), 8.54 (m, 1H), 8.01 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.26-7.23 (m, 2H), 6.90 (m, 1H), 5.89-5.87 (m, 2H), 5.14 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:7][CH2:6]2.S(=O)(=O)(O)[O-].[K+].[OH-].[Na+]>ClCCl.S([O-])([O-])(=O)=O.[Ni+2]>[CH3:23][N:22]([CH2:21][CH2:20][CH2:19][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[O:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]#[N:1])[CH:11]=[CH:10][C:9]1=2)[CH3:24]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(CN)ccc21
Agent: [Ni+2]
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reaction time: 96 h

Procedure:
To a stirred solution of 5-aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran (0.5 g, 1.5 mmol) in dichloromethane (10 mL) was added an aqueous solution of potassium bisulfate and sodium hydroxide (19 mL; 0.2 M in K2S2O8, 3.8 mmol; 0.4 M in NaOH, 7.6 mmol), followed by an aqueous solution of nickel sulfate (1.5 mL, 40 mM, 61 μmol). The mixture was stirred vigorously for 4 days, and was then filtered through celite. The filtrate was partitioned between aqueous sulfuric acid (2 M) and toluene. The aqueous layer was separated, and the pH of the mixture was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The solution was extracted with toluene, and this latter toluene extract was dried over magnesium sulfate and evaporated to give the free base of citalopram as a very pale yellow oil (0.35 g, 70%).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:5]2[CH2:6][N:7]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cc1
Yield: 59.4 %

Procedure:
A mixture of 400 mg of 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine and 600 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na2SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 518 mg of the desired product. M+1=439.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26].[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[CH:38]=CC(C=O)=[CH:41][C:30]=2[N:29]=1>C1COCC1>[CH:25]([C:24]1[CH:23]=[CH:38][C:31]2=[C:32]3[C:37](=[C:28]([NH2:27])[N:29]=[C:30]2[CH:41]=1)[N:36]=[CH:35][CH:34]=[CH:33]3)=[CH2:26]
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)nc(N)c1ncccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl triphenyl phosphonium iodide (6.0 eq.) was added nBuLi (7.0 eq.) at −78° C. The reaction mixture was allowed to warm to 0° C. and stirred for 30 minutes (deep orange color). The reaction was again cooled down to −78° C. and 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) (1.0 eq.) in THF was introduced dropwised to the reaction. The reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% EtOAc/Hexanes to give 8-vinylbenzo[f][1,7]naphthyridin-5-amine as a white solid: 1H NMR (acetone-d6): 1H NMR (acetone-d6): δ 9.00 (dd, 1H), 8.90 (dd, 1H), 8.41 (d, 1H), 7.84 (dd, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 6.91 (dd, 1H), 6.77 (br s, 2H), 5.97 (dd, 1H), 5.34 (dd, 1H). LRMS [M+H]=222.1.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([O:27][CH2:28][CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[Cl:26].[Li+].[OH-]>>[Cl:26][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:10]=[CH:11][C:6]=1[CH2:5][C@H:4]([O:27][CH2:28][CH3:29])[C:3]([OH:30])=[O:2]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1Cl)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1Cl)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH2:9][C:10]#[CH:11])[CH3:8])=[CH:4][CH:3]=1.ClC1C=CC=CC=1CN(CC#C)C>>[CH2:6]([N:7]([CH2:9][C:10]#[CH:11])[CH3:8])[C:5]1[CH:12]=[CH:13][CH:2]=[CH:3][CH:4]=1
Reactant: C#CCN(C)Cc1ccc(Cl)cc1
Agent: C#CCN(C)Cc1ccccc1Cl
Product: C#CCN(C)Cc1ccccc1

Procedure:
N-(4-chlorobenzyl)-N-methyl-2-propinylamine; N-(2-chlorobenzyl)-N-methyl-2-propinylamine;
Reaction SMILES: C1(C([NH:20][C:21]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=2[CH:23]=[O:24])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH:23]([OH:24])[C:31]([F:33])([F:32])[F:30]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1c(F)cccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1C(O)C(F)(F)F
Temperature: 25 °C
Yield: 175.3 %

Procedure:
To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[F:14].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)=[CH:23][CH:24]=2)=[O:7])=[CH:4][C:3]=1[F:14]
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (1.00 g, 3.8 mmol) in dry tetrahydrofuran at 0° C. under nitrogen was added dropwise (4-(tetrahydro-2H-pyran-2-yloxy)phenyl)magnesium bromide (7.6 mmol). After addition, the reaction mixture was let warm to room temperature, stirred for 2 h., quenched with saturated ammonium chloride, and extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated, and purified by column chromatography to give the desired product as a colorless oil (1.10 g, 76% yield).
Reaction SMILES: [I:1]I.[OH-].[K+].[CH3:5][O:6][P:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16](C(=O)C)[N:15]=[CH:14]2)(=[O:10])[O:8][CH3:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH3:5][O:6][P:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[I:1])(=[O:10])[O:8][CH3:9]
Reactant: II
Reactant: COP(=O)(OC)c1ccc2c(cnn2C(C)=O)c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(OC)c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
814 mg (2 eq-3.206 mmol) of iodine and 180 mg (2 eq-3.206 mmol) of ground potassium hydroxide are added to a solution of 430 mg (1 eq-1.603 mmol) of (1-acetyl-1H-indazol-5-yl)phosphonic acid dimethyl ester in 20 ml of dimethylformamide. The medium is stirred at ambient temperature over a weekend. Another portion of 814 mg of iodine and 180 mg of potassium hydroxide are added to the reaction mixture, which is continued to stir for an additional period of 3 hours at ambient temperature. 20 ml of a saturated sodium thiosulfate solution are added and the medium is stirred for 10 minutes. The reaction mixture is washed with 40 ml of water. The aqueous phase is treated with 4 times 50 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and then filtered and the solvent is evaporated off under reduced pressure in a rotary evaporator to obtain 458 mg of (3-iodo-1H-indazol-5-yl)phosphonic acid dimethyl ester.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C@:15]12[CH2:32][CH2:31][C@H:30]3[C@@H:20]([CH2:21][CH:22]=[C:23]4[C@:28]3([CH3:29])[CH2:27][CH2:26][C@H:25]([OH:33])[CH2:24]4)[C@@H:19]1[CH2:18][O:17][CH2:16]2.CC(C)=O.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:14][C@:15]12[CH2:32][CH2:31][C@H:30]3[C@@H:20]([CH2:21][C:22](=[O:3])[C:23]4[C@:28]3([CH3:29])[CH2:27][CH2:26][C:25](=[O:33])[CH:24]=4)[C@@H:19]1[CH2:18][O:17][CH2:16]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1COC2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4=CC(=O)CC[C@@]43C)[C@@H]1COC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30 μl of Jones reagent was added dropwise at 0° C. to a mixture of 10 mg of 16-oxaandrost-5-en-3β-ol and 0.5 ml of acetone, and the mixture was stirred at room temperature for 30 minutes. 2-propanol and 5% aqueous sodium bicarbonate solution were added to the reaction mixture and the insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure, water was added, and the product was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled out, and the resultant crude product was purified by TLC [developing solvent; chloroform acetone (19:1)] to obtain 3 mg of 16-oxaandrost-4-ene-3,6-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13].C(OCCO)C>>[CH:8]1([C:6]2[CH:7]=[C:2]([NH:12][NH2:13])[N:3]=[CH:4][N:5]=2)[CH2:10][CH2:9]1
Reactant: Clc1cc(C2CC2)ncn1
Reactant: NN
Solvent: CCOCCO
Solvent: O
Product: NNc1cc(C2CC2)ncn1

Procedure:
1.6 g (6.9 mmol) 4-chloro-6-cyclopropylpyrimidine [FR 1 519 069 (1966); Chem. Abstr. 71, 49965y, 1969] and 3.4 ml (3.5 g, 69.0 mmol) hydrazine hydrate are stirred at a bath temperature of 90° C. for 16 h. Ethylene glycol monoethyl ether is added to the cooled reaction mixture and the mixture is concentrated in vacuo. This operation is repeated once. The residue is then chromatographed over silica gel 60 (mobile phase: acetonitrile/water 8:2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(methylsulfonyl)indoline (intermediate-26) (0.160 g, 48.0%).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[N:12](COCC[Si](C)(C)C)[C:11]3[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:10]=3[N:9]=2)[CH:4]=1.CSC1NN=C(N2C3C=CC(C(F)(F)F)=CC=3N=C2)C=1>>[CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[NH:12][C:11]3[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:24][C:10]=3[N:9]=2)[CH:4]=1
Reactant: CSc1cc(-c2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)n[nH]1
Agent: CSc1cc(-n2cnc3cc(C(F)(F)F)ccc32)n[nH]1
Product: CSc1cc(-c2nc3cc(C(F)(F)F)ccc3[nH]2)n[nH]1

Procedure:
By proceeding in a similar manner to Example 230(a) above but using 2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [Reference Example 1(d)] there was prepared 2-(5-methylsulfanyl-1H-pyrazol-3-yl-5-trifluoromethyl-1H-benzoimidazole.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][CH2:31][OH:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)CCO
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=403.4 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and 3-hydroxy-propionic acid
Reaction SMILES: F[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[N:27][NH:28][CH:29]=1)=[O:24]>C(#N)C.CS(C)=O>[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH:29]=1)=[O:24]
Reactant: CNC(=O)c1cn[nH]c1
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CS(C)=O
Solvent: CC#N
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
PCT application WO 2012/149196 describes preparation of polymorph D by a relatively complicated procedure. First, a “cross coupling” reaction of 2-fluoroadenosine with N-methylpyrazol-4-carboxamide in an acetonitrile/dimethylsulfoxide mixture provides crude 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, which is then purified by reverse-phase chromatography using a methanol/water mixture. After concentrating at 150° C. under reduced pressure, polymorph D is obtained as a white solid substance containing variable amounts of water.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(O)C>[Fe].O>[S:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1)[C:12]#[N:13]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: N#CSc1ccc(N)c(N)c1
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a suspension of 2-nitro-4-thiocyanato-aniline, 22.3 g. of powdered iron, 40 ml. of 96% ethanol and 50 ml. of water a solution of 2,2 g. of ferrous(II)chloride and 4 ml. of water is added dropwise under stirring at the boiling point of the mixture. Stirring is continued for a further 10 minutes, whereupon the reaction mixture is filtered. To the filtrate 200 ml. of water are added. On cooling crystals precipitate, which are filtered off. Thus 12.3 g. of 4-thiocyanato-1,2-diamino-benzene are obtained. Yield: 74.5%. M.p.: 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:25])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C@H:11]([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:26]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:25])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C:11]([CH3:26])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)[C@H](C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2C(=O)C(C)(C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
A dried flask was charged under an argon atmosphere with a solution of the crude (2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one (622 mg) in tetrahydrofuran (16 ml) which was cooled to −75° C. Lithium diisopropylamide (1.54 ml, 3 mmol) was rapidly added, followed by iodomethane (502 mg, 3.5 mmol). After 15 minutes at −75° C. the reaction was complete. For the workup, the cold reaction mixture was quenched with a saturated ammonium chloride solution (15 ml) and extracted with a mixture of dichloromethane (40 ml) and water (15 ml). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 66/34 as the eluent. The (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one was obtained as a white solid (495 mg, 77% of theory). Mass (calculated) C21H24BrNO3 [418.334]; (found) [M+H]+=418, [M+2-H]+=420.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:7][C:6]=1[O:21][CH3:22])([CH3:3])[CH3:2].[ClH:23]>>[ClH:23].[CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][C:6]=1[O:21][CH3:22])([CH3:3])[CH3:2]
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1OC(C)C
Agent: Cl
Product: COc1cc(CCN)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
In a 50 mL round bottom flask was combined tert-butyl 4-isopropoxy-3-methoxyphenethylcarbamate (810 mg, 2.62 mmol) and HCl (4M in 1,4-dioxane) (6.5 mL, 26.2 mmol). The suspension was stirred at RT for two hours then concentrated in vacuo to afford 2-(4-isopropoxy-3-methoxyphenyl)ethanamine hydrochloride (643 mg) MS [M+H+]=210.3.