Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([OH:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc([N+](=O)[O-])c1O

Procedure:
4-Chloro-2-methoxyphenol (1.77 g) was dissolved in acetic acid (18 mL). To this solution, a separately prepared nitric acid solution (mixture of 70% nitric acid (1.88 mL) and acetic acid (5 mL)) was added under ice cooling with stirring. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain a crude product. This product was purified by silica gel chromatography (ethyl acetate:n-hexane=4:1 v/v) to obtain the title compound (1.8 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>CCCCCC.C(OCC)C>[F:15][C:16]([F:24])([F:23])[C:17]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under nitrogen atmosphere, a 500 mL glass flask was charged with 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether, followed by cooling to −78° C. At −78° C., 60 mL of a 1.6M solution containing 96.0 mmol of n-butyllithium in hexane was added dropwise by spending 1 hr, followed by aging at −78° C. for 1 hr. After confirming lithiation by gas chromatography, 16.6 g (100.0 mmol) of hexafluoroacetone was bubbled at −78° C., followed by stirring for 1 hr. After stirring, the reaction liquid was added to 400 mL of 2N hydrochloric acid to separate it into an organic layer and an aqueous layer. The aqueous layer was extracted with 100 mL of isopropyl ether. The combined organic layer was dried with anhydrous magnesium sulfate, followed by concentration with an evaporator and then solid distillation, thereby obtaining 23.0 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene (yield: 60%) represented by the following formula.
Reaction SMILES: O1CCCC1.[CH2:6]([NH2:8])[CH3:7].CS([C:12]1[N:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)=O.Cl>O1CCCC1>[CH2:6]([NH:8][C:12]1[N:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=2)[C:14](=[O:23])[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)[CH3:7]
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CCN
Agent: Cl
Solvent: C1CCOC1
Product: CCNc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethylamine tetrahydrofuran solution (2M, 2 ml) was diluted with tetrahydrofuran (2 ml), 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (100 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 10 min. The pH of the reaction mixture was adjusted to about 7 with 0.5M hydrochloric acid (about 4 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:42]3[CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40][CH2:41]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 13.9 %

Procedure:
A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.500 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.409 g, 1.5 eq.), 4,4-difluoropiperidine hydrochloride (0.269 g, 1.2), DIPEA (0.220 g, 1.2 eq) and HOBT (0.261 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry. The aqueous layer was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.60 g of crude compound. Purification by preparative TLC (eluting with MeOH/CH2Cl2) afforded 0.090 g compound which was further triturated using ether: petroleum ether to remove aliphatic impurity affording 0.06 g pure compound. Yield: 9.28%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.O>C(Cl)(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(Cl)c1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cc2ccc(Cl)cc2)cc(Cl)c1O

Procedure:
178.1 g (1.25 mol) 2-chloro-6-methylphenol and 80.5 g (0.5 mol) 4-chlorobenzyl chloride are dissolved in 300 ml dry chloroform. 40 g water-free, finely mortared ZnCl2 are subsequentlyadded.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(NS(=O)(=O)c2ccc(F)cc2)CC1
Reaction time: 6.5 h
Yield: 67058.9 %

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzenesulfonyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 20:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide (859 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][C:35](O)=[O:36].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:35](=[O:36])[CH2:34][N:18]2[CH2:19][CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]2=[O:16])[CH2:9][CH2:10]1
Reactant: Clc1cccc(Cl)c1CN1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C

Procedure:
To 1-(2,6-dichlorobenzyl)piperazine (0.045 g, 0.183 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.069 g, 0.183 mmol) and 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.054 g, 0.183 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.048 mL, 0.274 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, thin layer chromatography (hexanes/ethyl acetate 1:1) indicated formation of the product. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.10-7.38 (m, 13H), 4.19 (s, 2H), 3.71 (s, 2H), 3.48-3.59 (m, 4H), 3.33-3.40 (m, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.50-2.58 (m, 2H), 2.41-2.49 (m, 2H); MS (DCI+) m/z 522.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.[ClH:45]>C1COCC1>[ClH:43].[ClH:45].[ClH:43].[Cl:43][C:37]1[CH:36]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)[CH:40]=[C:39]([F:41])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 65 °C
Yield: 191.5 %

Procedure:
To a solution of tert-butyl (1-(5-((3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (85 mg, 0.14 mmol) in THF (5 mL) was added water (3 mL) and HCl (6 M in water, 2 mL, 12 mmol). The reaction mixture was heated at 65° C. for 3 h, cooled to room temperature and concentrated. The resultant residue was triturated with dichloromethane to give the desired product (55 mg, 64%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.31 (s, 1H), 8.31-8.23 (m, 2H), 8.10-8.03 (m, 2H), 7.95 (dd, J=9.4, 2.4 Hz, 1H), 7.22 (dd, J=11.5, 2.3 Hz, 1H), 7.18-7.11 (m, 2H), 4.14-4.08 (m, 2H), 3.98-3.86 (m, 2H), 3.83-3.74 (m, 1H), 2.84 (s, 3H), 2.79 (s, 3H), 2.71-2.60 (m, 1H), 2.47-2.36 (m, 1H). ESI MS m/z 506 [C27H25ClFN50O2+H]+; HPLC 97.4% (AUC), tR=9.62 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4]C=1C#N.S(=O)(=O)(O)O.[C:27]([OH:30])(=[O:29])[CH3:28]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:28]=1[C:27]([OH:30])=[O:29]
Reactant: CC(=O)O
Reactant: N#Cc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a suspension of 544 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile obtained by Example 100 in 2 mL of acetic acid and 3 mL of water was added 6 mL of concentrated sulfuric acid, and stirred at 110° C. for 12 hours. After allowing to cool, the reaction solution was added with ice, and extracted with a mixed solvent of 200 mL of ethyl acetate and 50 mL of tetrahydrofuran. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 491 mg of the title compound as pale brown crystals.
Reaction SMILES: [Li]CCCC.N12CCN(CC1)CC2.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN(C)[CH:23]=[O:24]>C(OCC)C.O>[CH:23]([C:16]1[C:15]([F:14])=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1ncccc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
Dry ethyl ether (500 mL), n-BuLi (1.6M in hexane, 62.5 mL, 0.1 mol), and dry 1,4-diazabicyclo[2.2.2]octane (DABCO) (11.56 g, 0.1 mol) were introduced into a 1 L flask under a dry N2 stream at -60° C. and the resulting cloudy solution was stirred for 1 hour at -20° C. The mixture was then cooled to -75° C. and an ethyl ether (50 mL) solution of 3-fluoropyridine (9.81 g, 0.1 mol) was added dropwise and stirring continued for 1 1/2 hours at -60° C. The mixture was recooled to -75° C., dry N,N-dimethylformamide (8.52 mL, 0.11 mol) dissolved in ethyl ether (50 mL) was added dropwise and the mixture stirred for 2 hours at -75° C. Water (175 mL) was introduced slowly at -10° C., the aqueous layer extracted with ethyl acetate (5×200 mL), and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal produced a dark brown oil which after vacuum distillation and purification by chromatography on silica gel provided 4.4 g (35%) of the titled product as an off-white crystalline solid:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([O:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:17]1[CH:18]=[CH:19][C:14]([O:20][CH3:21])=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccccc1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(CCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
A solution of 6-bromohexanoyl chloride (50 g, 0.2 mol) in dry dichloromethane (40 ml) was added dropwise over 5 minutes to a suspension of aluminium chloride (31 g, 0.2 mol) in dry dichloromethane (100 ml), keeping the temperature between 20-23° C. The mixture was stirred for 30 minutes at room temperature to give a yellow solution. Anisole (23 g, 0.2 mol) in dry dichloromethane (30 ml) was added and stirred for 20 hours at room temperature. Triethylsilane (59.9 g, 0.515 mol) was added over 10 minutes, maintaining the temperature between 25° C.-35° C. The solution was stirred for 60 minutes at room temperature and poured onto ice/water (200 g). The organic layer was washed with brine and water until the pH of the solution was neutral. Drying (MgSO4) and evaporation under reduced pressure gave a yellow oil which was distilled under reduced pressure at 90-110° C./0.5 mbar. Produce containing fractions were combined and purified by flash chromatography on silica gel using hexane as eluant to give a colourless oil (18.33 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[C:7](=[N:15]O)[C:6]=2[CH:17]=1.[Cl-].[NH4+:19].N>[Zn].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[CH:7]([N:15]=[C:5]3[CH2:6][CH2:17][CH2:2][CH2:3][CH2:4][NH:19]3)[C:6]=2[CH:17]=1
Reactant: ON=C1c2cc(Cl)ccc2CCc2sccc21
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Clc1ccc2c(c1)C(N=C1CCCCCN1)c1ccsc1CC2
Temperature: 25 °C

Procedure:
80.5 g of 6-chloro-9,10-dihydro-4-hydroxyimino-4H-benzo-[4,5]cyclohepta[1,2-b]thiophene, 105 g of zinc dust and 14 g of ammonium chloride are stirred with 1750 ml of 25% ammonia solution and 350 ml of ethanol for 3 hours at the boiling temperature. Upon cooling to room temperature, the undissolved portion is filtered off and is washed with benzene. 200 ml of concentrated caustic soda solution are added to the filtrate which is extracted with a mixture of ether/benzene 1:1. The organic phase is washed with saturated common salt solution, dried over magnesium sulphate and the solvent is removed by evaporation. The remaining 4-amino-6-chloro-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene is converted in ethanol into the hydrochloride. M.Pt. decomp. from 234°.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH:34]=[O:35])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([OH:6])=[O:35])[CH2:26]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C=O)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of sodium chlorite (1.85 g; 20.43 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.6 g; 13.37 mmol; 3.6 eq.) in water (10 mL) was added dropwise to a mixture of 2-methyl-2-butene (3.71 mL) and 3-(2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.03 g; 3.71 mmol; 1 eq.) in 1,4-dioxane (10 mL). and the reaction mixture was stirred at room temperature for 2 hours. The dioxane was evaporated in vacuo, the mixture diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off, washed with water and dried to afford the title compound (1.02 g, 94%) as a white solid. UPLC/MS: (MS−) 292.4 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[BH4-].[Na+]>CO>[OH:9][CH:3]1[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)C(=O)CCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C(=O)CCCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2,2-dimethylcyclohexane-1,3-dione (2.00 g, 14.3 mmol) in MeOH (20 mL) was added sodium borohydride (135 mg, 3.58 mmol) portion-wise at 0° C. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (1.6 g, crude). MS (ESI) m/z 143.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[Br:14][C:13]1[C:2]([NH:1][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[C:3]([CH:10]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=1)[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCCC(=O)Cl
Reactant: CCOC(=O)c1cc(Br)c(N)c(CN(CC)CC)c1
Solvent: c1ccccc1
Product: CCCC(=O)Nc1c(Br)cc(C(=O)OCC)cc1CN(CC)CC

Procedure:
3 gm of 2-Amino-3-bromo-5-carbethoxy-N,N-diethyl-benzylamine were dissolved in 30 ml of benzene, and the solution was heated for 30 minutes with 3 ml of butyric acid chloride at 50°C. Thereafter, the mixture was evaporated to dryness in vacuo, and the residue was purified by chromatography on silicagel (eluant: benzene/ethyl acetate = 6:1), yielding 3-bromo-2-butyrylamino-5-carbethoxy-N,N-diethyl-benzylamine, which was converted into its hydrochloride, m. p. 134°C, with ethanolic hydrochloric acid.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.ClCCl>>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Reference Intermediate R5, 175 mg) in dry dichloromethane (DCM) (6 mL) TFA (2 mL, 26.0 mmol) was slowly added and the reaction mixture was stirred for 1 h at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a colourless solid (122 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Cl.ClC[C:46]1[N:50](C)[N:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:50]([CH3:46])[N:49]=[CH:48][N:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncnc1CCl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Product: Cn1ncnc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and isolated as colorless gum. MS (m/e): 378.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:2]([F:1])=[C:3]2[C:8]([N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:7])[C:4]=12)=[O:9]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: CC(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1=O
Temperature: 20 °C

Procedure:
3,6-Difluoro-N-isobutylphthalimide is prepared as described in Example 2, starting with 5.0 g of 3,6-difluorophthalic anhydride, 2.7 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 50 cm3 of toluene. The reaction mixture is refluxed for 3 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in 50 cm3 of saturated aqueous sodium bicarbonate solution and washed 3 times with 80 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 6.41 g of 3,6-difluoro-N-isobutylphthalimide are thus obtained in the form of a pale yellow solid. (Rf=0.74, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[K+].[Br:22]Br>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])=[C:8]([Br:22])[C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C#N)cc1CC(C)(C)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCCn1nc(C#N)c(Br)c1CC(C)(C)O
Temperature: 0 °C
Yield: 53.5 %

Procedure:
The method described in Part F of Examples 1 through 4 was used to treat 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (18 g, 81 mmol) with potassium acetate (16.7 g, 171 mmol) and bromine (4.6 mL, 89 mmol). After the acetic acid was removed under reduced pressure, the residue was diluted with dichloromethane (100 mL) and adjusted to pH 12 with the addition of 50% w/w aqueous sodium hydroxide and ice while maintaining the temperature at 0° C. The resulting mixture was extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (60I cartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 13 g of 1-butyl4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile as a yellow oil.