Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2.O.C(OCC)(=O)C.[CH3:37][N:38](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:37]([C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:18][CH2:19]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2)#[N:38]
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3c(Br)ccc4cccc2c34)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2cccc3c2c1CC3N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[1-(3-Bromoacenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (1.25 g) was dissolved in N,N-dimethylformamide (16 ml), zinc cyanide (380 mg) and tetrakistriphenylphosphinepalladium (1.6 g) were added, and the mixture was stirred at 110° C. for 1 hr. After allowing to cool, water and ethyl acetate were poured into the reaction mixture, and the mixture was subjected to celite filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and recrystallized from acetone to give the title compound (1.0 g).
Reaction SMILES: N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.O1CCCC1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[C:35](/[N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)\[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[C:35](/[N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)\[CH:36]([OH:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: B
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
In a nitrogen atmosphere, 3.5 ml of a chloroform solution containing 0.233 g (0.86 mmole) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol was added at -60° C. to 0.87 ml (0.87 mmole) of a 1.0M borane-tetrahydrofuran solution, and the temperature of the resulting solution was raised to room temperature over 2 hours. Thereafter, 2 ml of a chloroform solution containing 0.164 g (0.57 mmole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one was added to this solution at room temperature, and stirring was carried out for 24 hours. After-treatment was carried out in the same manner as in Example 1 to obtain 0.164 g of (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The conversion was 87.0%, and the composition of the product was: E-form alcohol, 97.3% and Z-form alcohol, 2.7%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 87.2% and (-)-isomer 12.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:5]2=[C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]2=[C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]2=1
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: O
Solvent: CC(C)=O
Product: Fc1ccc2[nH]c3c4[nH]c5ccc(F)cc5c4c4c5cc(F)ccc5[nH]c4c3c2c1
Yield: 64.7 %

Procedure:
15 ml of acetone was poured into a 200 ml three-neck flask, and 1.35 g of 5-fluoroindole was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 33.6 g of cupric chloride anhydrate and 13.5 g of water in 55 ml of acetone and then agitating the resultant mixture for 5 minutes. Then the prepared oxidant solution was dripped into the 5-fluoroindole solution over 2 hours, and the resultant mixture was agitated for 5 hours at the temperature of 40° C. Color of the reaction solution changed from white to dark blue with slight heat generation. pH of the reaction solution was less than 1. After the end of the reaction, the reaction solution was suction-filtered with a Perforated funnel, and the filtrate was washed with acetone and then methanol, and was dried to obtain 0.86 g of 2,9,14-trifluoro-6,11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole (5-fluoroindole trimer) (yield: 64%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and to be 0.88 S/cm. The result of elemental analysis was: <C8.00H3.95N1.10Cl0.10>3.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:23]([O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[CH2:23]([O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([Cl:12])=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:11])[N:39]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1ccc(-c2nc(-c3c(Cl)cccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
A mixture of 1.10 g of N-methyl-N-phenylsulfonyl-2,6-dichlorobenzohydrazonoyl chloride, 0.70 g of 4-decyloxybenzonitrile, 0.4 g of anhydrous aluminium chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.40 g of the given compound (melting point: 60.0°-64.0° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:40](Br)[CH:41]=[CH2:42]>CC(C)=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:42][CH:41]=[CH2:40])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Temperature: 0 °C
Yield: 60 %

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (2.50 g) is dissolved in acetone (20 ml), and thereto are added potassium carbonate (2.13 g) and allyl bromide (933 mg), and the mixture is refluxed for 6 hours. After cooling, the reaction mixture is poured into ice-water, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (1.63 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:16][O:17][CH2:18][CH3:19])[CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:20][C:21](=[N:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[S:22][CH3:23].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[N:16][O:17][CH2:18][CH3:19])[CH2:12][C:13](=[O:15])[NH:20][C:21](=[N:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[S:22][CH3:23])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CSC(N)=NC(=O)OC(C)(C)C
Reactant: C=CCOc1ccc(C(CC(=O)O)=NOCC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(C(CC(=O)NC(=NC(=O)OC(C)(C)C)SC)=NOCC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
A mixture of 3-(4-(Allyloxy)phenyl)-3-(ethoxyimino)propanoic acid from Step C (850 mg), tert-butyl amino(methylthio)methylenecarbamate (675 mg), Py.Bop (2.01 g), and triethylamine (0.68 mL) in dichloromethane (1.8 mL) was stirred at room temperature for 12 h. The crude reaction mixture was purified directly by Boitage flash chromatography eluting with 15-30% ethyl acetate/85-70% hexanes to give the title compound as a white solid (1.14 g). HPLC retention time: 2.37 min (method A). MS (ESI) (M+Na)+ 436.25.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH:16]([C:18]([OH:20])=O)[S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([CH:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:17]1)=[O:20])[CH3:22]
Reactant: CCNCC
Reactant: O=C(O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
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: CCN(CC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
To 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid (1.65 g, 6 mmol) in CH2Cl2 (15 ml) were added diethylamine (0.7 ml, 7 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (2.75 g, 6 mmol) and diisopropylethylamine (3.1 ml, 18 mmol). The reaction was stirred at room temperature for 3 days. The reaction mixture was diluted with CH2Cl2 (100 ml), washed with 1N HCl, saturated NaHCO3 soln, brine, dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with 50% EtOAc/petroleum ether to give 1.07 g (54%) of 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid diethylamide as a yellow solid. 1H NMR (CDCl3) δ 9.23 (1H, s), 7.33 (1H, dd), 7.20 (1H, dd), 7.69-7.08 (5H, m), 6.66-6.72 (1H, m), 5.33 (1H, s), 3.34-3.76 (4H, m), 1.39 (3H, t), 1.37 (3H, t).
Reaction SMILES: C(N(C)CCC(O)CCCC)C1C=CC=CC=1.[C:18]([O:22][C:23](=[O:37])[N:24]([CH2:26][CH2:27][C:28](=[O:36])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:37])[N:24]([CH2:26][CH2:27][CH:28]([OH:36])[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(CCC(=O)CC1CCCCC1)C(=O)OC(C)(C)C
Agent: CCCCC(O)CCN(C)Cc1ccccc1
Product: CN(CCC(O)CC1CCCCC1)C(=O)OC(C)(C)C

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-ol, (4-cyclohexyl-3-oxo-butyl)-methyl-carbamic acid tert-butyl ester affords the title compound: 1H NMR (CDCl3) δ 3.90-3.80 (m, 1H), 3.62-3.52 (m, 1H), 2.88-2.96 (m, 1H), 2.83 (3H), 1.80-1.60 (m, 6H), 1.56-1.32 (m, 3H), 1.47 (s, 9H), 1.31-1.08 (m, 4H), 0.98-0.77 (m, 2H),
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([CH3:37])[N:32]1[C:38]1[N:42]2[CH:43]=[C:44]([O:47][C@H:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[C@@H:51]([NH2:58])[CH2:50][CH2:49]3)[CH:45]=[CH:46][C:41]2=[N:40][N:39]=1.C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CCOS(C)(=O)=O)C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:15]([C:12]([CH3:14])([CH3:13])[C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:58][C@@H:51]2[C:52]3[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=3)[C@H:48]([O:47][C:44]3[CH:45]=[CH:46][C:41]4[N:42]([C:38]([N:32]5[C@H:31]([CH3:30])[CH2:36][CH2:35][CH2:34][C@@H:33]5[CH3:37])=[N:39][N:40]=4)[CH:43]=3)[CH2:49][CH2:50]2)=[O:27])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=1)#[N:16]
Reactant: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Agent: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 20e and Intermediate 3 in an analogous fashion to the procedure described for Intermediate A step d. LCMS (Method 3): Rt 3.61 min, m/z 704.5 [MH+].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12]C(=O)C)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH3:2].Cl>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH3:2]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(NC(C)=O)ccc21
Agent: Cl
Solvent: CO
Product: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N)ccc21

Procedure:
Crude N-{1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl}acetamide is treated with 10% aqueous HCl (20 mL) in methanol (10 mL) at reflux for 1.5 h. After cooling, the methanol is removed in vacuo, and the aqueous layer washed with ethyl acetate. The aqueous layer is adjusted to pH 10 with 3 N NaOH, then extracted with ethyl acetate (3×), and the combined organic extracts washed with water (2×) then saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole. LCMS MH+354.4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]I)[CH:3]=1.[CH2:22]([NH:24][CH2:25][CH2:26][OH:27])[CH3:23].Cl>O1CCCC1.C(OCC)C.ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][OH:27])[CH:3]=1
Reactant: CCNCCO
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CCO)CCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1
Yield: 65.4 %

Procedure:
A solution of the product from Example 1 step (c) (200 mg) and 2-(ethylamino)ethanol (163 mg, 0.14 ml) in tetrahydrofuran (5 ml) was stirred for 2 days. The solvent was removed in vacuo and the residue dissolved in water and aqueous potassium carbonate and extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give an oil. To a solution of this amine in diethyl ether-dichloromethane was added a 1M solution of hydrogen chloride in diethyl ether. The crystals that formed were collected and dried to afford the title compound as a white solid (65 mg). M.p. 141-144° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.O>[Si:27]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[NH:8][N:9]=2)=[CH:12][CH:13]=1)([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: Nc1ncnc2[nH]nc(-c3ccc(O)cc3)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2n[nH]c3ncnc(N)c23)cc1
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To a stirred solution of compound (4) (5.25 g, 23.1 mmol) and imidazole (3.85 g, 57.8 mmol) in dry DMF (70 mL) was added TBDMSCl (4.19 g, 27.7 mmol). After 16 hr, further aliquots of imidazole (1.93 g, 28.9 mmol) and TBDMSCl (2.10 g, 13.9 mmol) were added and the mixture stirred for 4 hr. The reaction mixture was diluted with water (200 mL) and the resulting precipitate was collected by filtration, washed with water (200 mL) and heptane (300 mL) to afford the title compound (5) (7.31 g, 93%) as a brown solid: m/z 344 (M+H)+ (ES+).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][OH:6].[F:11][C:12]([F:19])([F:18])[C:13]([F:17])=[C:14]([F:16])[F:15].FF>CCOCC.O>[CH:7]([C:4]([CH2:5][O:6][C:14]([CH:13]([C:12]([F:19])([F:18])[F:11])[F:17])([F:16])[F:15])([F:10])[F:3])([F:9])[F:8]
Reactant: OCC(F)(F)C(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Agent: FF
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: FC(F)C(F)(F)COC(F)(F)C(F)C(F)(F)F
Yield: 80 %

Procedure:
Into a 3-liter autoclave were poured 84 g (1.35 mol) of KOH, 800 ml of H2O and 600 g (4.5 mol) of 2,2,3,3-tetrafluoropropanol: CHF2CF2CH2OH. Then, 681 g (4.5 mol) of hexafluoropropene: CF2═CFCF3 was introduced thereto. After completion of the reaction, the reaction solution was separated into two layers, and the lower layer was washed with water three times to separate the solution. After that, refining by distillation was carried out, and 1,015 g (3.6 mol) of a fluorine-containing chain ether (B1a): CHF2CF2CH2OCF2CHFCF3 was obtained (yield 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][C:22]([NH2:25])=[C:21]([O:26][CH:27]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=4[Cl:37])[CH3:28])[N:20]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[O:39]1CCOCC1>C(Cl)Cl>[C:27]([OH:39])(=[O:26])[CH3:29].[Cl:37][C:30]1[C:31]([F:36])=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[C@H:27]([O:26][C:21]1[C:22]([NH2:25])=[N:23][CH:24]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[N:20]=1)[CH3:28]
Reactant: CC(Oc1nc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C1COCCO1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)O
Product: C[C@@H](Oc1nc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (265 mg, 0.48 mmol) in CH2Cl2 was added 4N HCl/dioxane (4 mL). The mixture was stirred at ambient temperature for one hour. After evaporation, the residue was dissolved in methanol (2.5 mL), and was purified on a reverse phase C-18 reparative HPLC eluting with acetonitrile/water containing 0.1% acetic acid with a linear gradient of 10%-40%. After lyophilization, 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrazin-2-ylamine acetate was obtained as a white solid (125 mg, 51% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(O)C.Cl.[CH3:16][NH:17][CH3:18]>C(N(CC)CC)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 130 °C
Reaction time: 20 h
Yield: 17390.1 %

Procedure:
5-Chloro-2-nitroaniline (50 g; 0.29 mol) was added to a 5 L bomb followed by ethanol (1.1 L) at 0-5° C. Dimethylamine hydrochloride (130 g; 1.59 mmol) was added in one portion followed by triethylamine (260 ml) and the bomb quickly sealed. The bomb was heated to 130° C. with stirring at 4 bar for 20 hours. The reaction mixture was then allowed to cool to room temperature and the ethanol was removed under vacuum. 2 M sodium hydroxide solution (1 L) was added to the crude residue and this was extracted with ethyl acetate (1×1.3 L then 2×500 ml). The combined organic layers were washed with brine (150 ml), dried (magnesium sulphate), filtered and evaporated to give the 5-dimethylamino-2-nitroaniline (50.1 g, 96%).
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: OC1CCCCC1
Reactant: C=CN=C=O
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are introduced into a reaction vessel and heated to 40° C. A mixture of 110 parts of cyclohexanol and 89.5 parts of ethyl acetate (containing 0.02% of dibutyl-tin dilaurate as catalyst) is added in the course of 1 hour. The mixture is then allowed to react for 2 hours at 40° C. A pale yellow solution is obtained, from which the reaction product crystallises out on cooling. Blocked isocyanate content: 11.7%.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:24]3=[N:25][C:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=[C:23]3[C:22]([CH3:37])([CH3:36])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:38])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:47]>>[ClH:47].[CH2:29]([C:26]1[N:25]=[C:24]2[N:20]([C:18](=[O:19])[CH2:17][N:11]3[CH2:10][C@@H:9]([CH3:38])[NH:8][CH2:13][C@@H:12]3[CH2:14][O:15][CH3:16])[CH2:21][C:22]([CH3:36])([CH3:37])[C:23]2=[CH:28][CH:27]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(Cc3ccccc3)nc21
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1CN[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(Cc3ccccc3)nc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(2R,5R)-4-[2-(6-Benzyl-3,3-dimethyl-2,3-dihydro-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-ethyl]-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.38 mmol) was dissolved in DCM (10 mL) and placed under a nitrogen atmosphere. TFA (2 mL) was added to the reaction which was stirred at room temperature for 40 minutes. The reaction was concentrated in vacuo. The residue was partitioned between DCM (100 mL) and aqueous sodium hydrogen carbonate (100 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography: (silica; 30 g packed in DCM and eluted with 5% MeOH in DCM-5-10% MeOH:DCM:0.5% NH4OH).gave product. This material was dissolved in EtOAc and the solution treated with 2M HCl in Et2O and concentrated in vacuo giving a white solid which was dried in an oven at 40° C. overnight giving the title compound (132 mg). 1H NMR (Me-d3-OD): 7.60 (1H, s), 7.33 (4H, s), 7.24 (1H, s), 7.03 (1H, s), 4.76 (1H, d), 4.67-4.54 (1H, m), 4.10 (2H, d), 3.84 (3H, s), 3.53 (6H, s), 3.26 (1H, d), 3.20 (3H, s), 1.38 (9H, s). MS: [M+H]+=423.