Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:24])([F:23])/[C:17](/[CH3:22])=[CH:18]\[C:19](Cl)=[O:20].C(Cl)(=O)C(Cl)=O.FC(F)(F)/C(/C)=C\C(O)=O>C1(C)C=CC=CC=1>[C:1]([N:5]([C:19](=[O:20])/[CH:18]=[C:17](\[C:16]([F:24])([F:23])[F:15])/[CH3:22])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(=C/C(=O)Cl)C(F)(F)F
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: C/C(=C/C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: C/C(=C/C(=O)N(NC(=O)c1ccccc1)C(C)(C)C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g,) in 2 ml toluene was added dropwise to a solution of beta-trifluoromethylcrotonyl chloride (prepared by addition of oxalyl chloride (1.3 g) to a solution of 1.5 g beta-trifluoromethylcrotonic acid in 5 ml toluene at 23° C.). After 30 minutes at 23° C., the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 ml) and ether (20 ml). The ether layer was evaporated under reduced pressure to about 10 ml and the excess hydrazine was removed by filtration. The filtrate was evaporated to give N'-t-butyl-N-benzoyl-N'-(beta-trifluoromethylcrotonyl)hydrazine as a colorless oil.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[CH:14]=[CH:13][C:8]2[CH:9]=C(C)[O:11][C:7]=2[C:6]=1[CH2:15][CH2:16][CH3:17].CSC>>[F:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[O:1])=[C:7]([OH:11])[C:6]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(F)ccc2cc(C)oc12
Reactant: O=[O+][O-]
Solvent: CSC
Product: CCCc1c(F)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Ozone was conducted at -78° into a solution of 4.8 g (25 mmol) of 6-fluoro-2-methyl-7-propyl-benzofuran until the colour became blue. Subsequently, argon was conducted through the solution which was then treated at -78° with 10 ml (136 mmol) of dimethyl sulfide. After warming to room temperature the solution was concentrated in a vacuum and the residue was dissolved in 40 ml of ethanol. After the addition of 20 ml of 3% sodium hydrogen carbonate solution the mixture was stirred at 70° for 30 minutes. Subsequently, the mixture was poured on to 200 ml of ice-water, made acid with 10% HCl and extracted three times with 150 ml of diethyl ether each time. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane). There were obtained 3.3 g (72%) of 4-fluoro-2-hydroxy-3-propyl-benzaldehyde as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC(C=O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (1.50 g, 6.66 mmol) in CH2Cl2 (50 mL) at 0° C. was treated with Dess-Martin periodinane (2.91 g, 6.66 mmol). The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction was quenched with aqueous 20% Na2S2O3 (100 mL) and aqueous saturated NaHCO3 (100 mL) and then stirred for 10 minutes. The CH2Cl2 layer was separated and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a cloudy colorless oil. The crude product was dissolved in 100 mL of 1:1 EtOAc/hexanes, filtered through a pad of silica gel, washed with 200 mL of 1:1 EtOAc/hexanes. The filtrate was concentrated to give 1.07 g (72%) of 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde as a clear colorless oil, which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 4.15-4.00 (m, 2H), 3.30-3.20 (m, 2H), 2.86 (septet, 1H, J=7.0 Hz), 2.55-2.45 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.65 (m, 2H), 1.26 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:16])([CH2:13][CH2:14]O)[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]([O:9][CH2:14][CH2:13][C:11]([CH3:12])([OH:16])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(O)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(O)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Three parts of benzoic acid was mixed with 2.6 parts of 2-methyl-butane-2,4-diol, 0.6 part of 4-dimethylaminopyridine and 45 parts of dehydrated tetrahydrofuran. To the obtained mixture, 5.6 parts of N,N′-dicyclohexylcarbodiimide was added, and then the obtained mixture was stirred at room temperature for 24 hours. The resultant mixture was filtrated and the filtrate was concentrated. To the residue, 33 parts of methyl tert-butyl ether was added and then, 17 parts of 2% aqueous oxalic acid solution was added. The resultant mixture was stirred and filtrated. The filtrate was separated into an organic layer and an aqueous layer. The organic layer was washed five times with ion-exchanged water and then dried over 3.1 parts of magnesium sulfate. The mixture was filtrated and the obtained filtrate was concentrated. The obtained residue was mixed with 6 parts of methyl tert-butyl ether and the resultant mixture was filtrated. The filtrate was concentrated to obtain 4.8 parts of 3-methyl-3-hydroxybutyl benzoate as colorless oil. This compound is called as Compound (G).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:18](=[O:31])[C:17]=1[Br:32])C.[OH-].[Na+].CO.O>C1COCC1>[Br:32][C:17]1[C:18](=[O:31])[N:19]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:20]([CH3:22])=[CH:21][C:16]=1[O:15][CH2:14][C:8]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2OCC(=O)O)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 59.5 %

Procedure:
A solution of ethyl[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetate (from Step 3) (0.62 g, 1.18 mmol), 1.5 N NaOH solution in 1:1 MeOH:water (1.2 mL, 1.77 mmol), and THF (1.2 mL) were refluxed at 60° C. for 1 h. The solution was concentrated on a rotary evaporator, cooled, and 5% citric acid added. The solid precipitate was filtered and dried in vacuo. Product obtained as a pale yellow solid (0.35 g, 60%). 1H NMR (CD3OD/400 MHz) δ7.59 (m, 1H), 7.49 (m, 1H), 7.22 (m, 2H), 6.75 (m, 2H), 6.72 (s, 1H), 5.43 (s, 2H), 4.66 (s, 2H), 2.07 (s, 3H). ESHRMS m/z 498.0143 and 500.0186 (M+H calculated for C21H16BrF3NO5 requires 498.0158 and 500.0141).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:9]=[CH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][N:28]=1)CCC>C1(C)C=CC=CC=1.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>[N:13]1([CH2:12][CH2:11][N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[C:3]3[CH:10]=[N:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Clc1ncnc2c1cnn2CCN1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1coc(-c2ncnc3c2cnn3CCN2CCCCC2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.188 mmol), 2-(tri-n-butylstannyl)oxazole (0.059 ml, 0.282 mmol) in toluene (3 mL) was introduced in a microwave vial. It was degassed by argon for 30 minutes followed by the addition of Pd(Ph3P)4 (22 mg, 19 mmol) after which the mixture was degassed for 10 additional minutes. The mixture was stirred at 100° C. for 30 min under microwave irradiation (150 W). The solvent was removed and the crude thus obtained was purified by flash chromatography to provide 2-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxazole as a cream-colored solid (37 mg, 0.12 mmol, 66%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:28])([F:27])[CH2:6][N:7]([C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][N:20]=[C:19]([Cl:26])[N:18]=1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>C(O)(=O)C.[Fe]>[Cl:26][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:4](=[O:3])[C:5]([F:28])([F:27])[CH2:6][N:7]([C@@H:8]3[CH2:10][C@H:9]3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[N:18]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1C[C@H]1c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N([C@@H]2C[C@H]2c2ccccc2)CC1(F)F
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution of 11.8 g (0.028 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(trans-2-phenyl-cyclopropyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-287) in 180 mL of acetic acid was added 11 g (0.20 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 7.95 g of 2-chloro-7,7-difluoro-9-(trans-2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-287) as a yellow foam.
Reaction SMILES: [CH2:1]1[O:5][C@H:4]([CH2:6][OH:7])[C@@H:3]([CH2:8][OH:9])[CH:2]1[N:10]1[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]1.[I:18](O)(=O)=O.II>O.C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH2:1]1[O:5][C@H:4]([CH2:6][OH:7])[C@@H:3]([CH2:8][OH:9])[C@@H:2]1[N:10]1[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([I:18])=[CH:11]1
Reactant: [O-][I+2]([O-])O
Reactant: Nc1ccn(C2CO[C@H](CO)[C@H]2CO)c(=O)n1
Agent: II
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1nc(=O)n([C@@H]2CO[C@H](CO)[C@H]2CO)cc1I
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To a solution of [3S-(3α,4β,5α)]-4-amino-1-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-2(1H)-pyrimidinone (96.5 mg, 0.4 mmol) in water (160 ml), acetic acid (320 μl) and carbon tetrachloride (80 μl) was added iodic acid (36 mg, 0.204 mmol) and iodine (60 mg, 0.236 mmol). The resulting mixutre was heated at 50° C. for 2 hours and it was then concentrated in vacuo to yield a dark residue. The excess iodine was removed from the residue by azeotroping several times with methanol. The crude material was dissolved in water (3 ml), and the pH was adjusted to 7 with 1N sodium hydroxide. The aqueous mixture was purified on a CHP-20P resin column (Mitsubishi Chemical Co., 75-150 μ, 20 ml) eluting with water (150 ml) and then 5% acetonitrile/water (300 ml). The appropriate fractions were combined, the volatiles were removed in vacuo, and the residue dissolved in water and lyophilized to give the title compound (55 mg) as a colorless solid. Proton NMR (270 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.65 (brs, 1H), 6.50 (brs, 1H), 4.92 (t, J=5.2 Hz, 1H), 4.87 (m, 1H), 4.80 (t, J=5.2 Hz, 1H), 3.60-3.90 (m, 4H), 3.51 (m, 3H), 2.24 (m, 1H); M.P.=212°-216° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Nc1cc(F)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1ccc(F)cc1N
Yield: 63.1 %

Procedure:
Following General Procedure A, the title compound (1.8 g, 60%) was prepared from 2-amino-4-fluorobenzenethiol (1.4 g, 9.79 mmol) and methyl 2-(bromomethyl)benzoate (2.2 g, 9.79 mmol), K2CO3 (4.0 g, 29.4 mmol) in DMF (50 ml).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)=[O:17])[CH3:14].[Cl:30][CH:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:13]([O:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Cl:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])[CH3:14]
Reactant: CCCCCC(O)Cl
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 73.4 %

Procedure:
69.2 g (343 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added to a solution of 95.4 g (343 mmol) of (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoic acid, 4.27 g (34.3 mmol) of 4-dimethylaminopyridine in 1.5 L of dichloromethane at 0° C. To this mixture, 46.7 mL (343 mmol) of chlorohexanol in 100 mL of dichloromethane are incorporated at 10° C. The solution is allowed to stir at room temperature for 22 hours. The reaction mixture is then partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue using toluene yielded 89.3 g (72%) of pure 6-chlorohexyl(2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoate as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1.Br[CH2:34][C:35]([NH:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH:25]3[CH2:27][CH2:26]3)[C:21]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]3[N:19]=2)=[CH:4][C:5]([C:15]#[N:16])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:10][C:9]1=[O:14]
Reactant: CNC(=O)CBr
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCNCC2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To solution of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 628)(20 mg, 0.045 mmol) in DMF (0.5 mL) was added 2-bromo-N-methylacetamide (13.54 mg, 0.089 mmol) followed by K2CO3 (73.9 mg, 0.535 mmol) at room temperature and stirred at room temperature for 1 h, LC-MS indicated completion. Purification via preparative HPLC gave the title compound as a yellow solid (5.9 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13]/[CH:12]=[CH:11]/[CH2:10][Br:9]
Reactant: Oc1ccccc1F
Reactant: BrC/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccccc1OC/C=C/CBr

Procedure:
100 g (0.9 mole) of 2-fluorophenol and 477 g (2.7 moles) of trans-1,4-dibromobut-2-ene were stirred under reflux with 70 g of K2CO3 in 500 ml of acetone for 5 hours. The mixture was filtered, and acetone was evaporated off under reduced pressure, the residue was taken up in methylene chloride, the solution was washed four times with aqueous 1 N NaOH solution, and the methylene chloride phase was dried with sodium sulfate and freed from unreacted 1,4-dibromobutene under reduced pressure. 175 g of trans-1-(2-fluorophenoxy)-4-bromobut-2-ene remained.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8].O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[C:13]([O:12][C:10]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:4][C:3]([OH:17])=[O:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)CN(CC(C)C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CN(CC(=O)O)C(=O)OC(C)(C)C
Yield: 39.9 %

Procedure:
Nα-(tert-Butyloxycarbonyl)-Nα-(2-methylpropyl) glycine methyl ester (960 mg, 3.91 mmol) was dissolved in THF/H2O (9:1, 25 ml). Lithium hydroxide monohydrate (492 mg, 11.7 mmol) was added. After 18 h at room temperature the reaction mixture was diluted with ethyl acetate (100 ml). This solution was washed with 1M HCl, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (360 mg, 1.56 mmol, 40%).
Reaction SMILES: [C@H:1]12[N:8](C(OC(C)(C)C)=O)[C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:16]([O:18][CH3:19])=[O:17].Cl>CCO.O1CCOCC1>[C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)C1CC[C@H]2CC[C@@H]1N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To (1S,5S)-8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (5.49 g) in EtOH (1 mL) was added 4M HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. Concentrated to give crude product (3.45 g).
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.06, 6.88, 5.61, 4.28, 2.97-2.80, 2.54, 2.05-1.92, 1.74, 1.49-1.21, 0.87; HRMS (FAB) calcd for C19H26BrN3S+H 408.1109, found 408.1108.
Reaction SMILES: [OH-].[Na+].ClC1C=CC(S([N:13]2[C:17]3[CH2:18][CH:19]4[N:24]([S:25]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:23]([C:16]=3[CH:15]=[N:14]2)[CH2:22][CH:21]([C:35]#[N:36])[CH2:20]4)(=O)=O)=CC=1.ClC1C=CC(S(N2C=C3C4N(S(C5C=CC(Cl)=CC=5)(=O)=O)C(CC3=N2)CC(C#N)C4)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([S:25]([N:24]2[CH:19]3[CH2:18][C:17]4[NH:13][N:14]=[CH:15][C:16]=4[CH:23]2[CH2:22][CH:21]([C:35]#[N:36])[CH2:20]3)(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: N#CC1CC2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: N#CC1CC2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydroxide (130 μL of a 3N aqueous solution) was added to a solution of 1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile and 2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile (61) (69 mg, 0.13 mmol) in THF (0.5 mL) and the resulting solution was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 10-[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile (62). MS (ESI) 363.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 5.38 (bs, 1H), 4.61-4.52 (m, 1H), 2.93 (dd, J=17.0, 6.6 Hz, 1H), 2.71-2.52 (m, 2H), 2.32-1.98 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[CH:25]=[C:24]([CH:26]=[O:27])[N:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[CH2:29]([CH:28]([N:23]1[C:21]2[N:22]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[N:18]=[CH:19][C:20]=2[CH:25]=[C:24]1[CH2:26][OH:27])[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)n1c(CO)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (20 mg, 0.046 mmol) in MeOH (1 mL) is added NaBH4 (3.5 mg, 0.092 mmol). The reaction mixture is stirred for 1 h and concentrated in vacuo. The residue is purified by preparative HPLC to give 15 mg of 1-(4-{4-[7-(1-ethyl-propyl)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone.