Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg]CCCC)CCC.C([Li])CCC.[O:28]=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>CCCCCCC.CCCCCC.C1COCC1>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)([OH:28])[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C3(C(=O)O)CC3)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1000.0 mg, 0.0041480 mol) in tetrahydrofuran (30 mL, 0.4 mol) was cooled below −20° C. under a N2 atmosphere and dibutylmagnesium in heptane (1.0 M, 2.2 mL) was slowly added to the solution while the reaction temperature was maintained below −20° C. Then 2.5 M of n-butyllithium in hexane (1.8 mL) was slowly added to the mixture below −20° C. under effective stirring. After stirring below −20° C. for 1 h, a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.909 g, 0.00456 mol) in THF (20.0 mL) was added to the mixture below −20° C. After stirring below −20° C. for 1 h, the reaction was quenched with ammonium chloride. The product was extracted with EtOAc and the combined extract was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and then purified by Combiflash, eluting with 5% methanol in methylene chloride.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[CH3:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:32]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromo-4-methylpyridine.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[NH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[N:22]([CH3:28])[N:21]=1.ClCCl>ClCCl.C(OCC)(=O)C.CN(C=O)C>[CH3:26][N:25]([CH3:27])[C:23]1[N:22]([CH3:28])[N:21]=[C:20]([NH:19][CH2:18][CH2:17][NH:16][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[N:24]=1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CN(C)c1nc(NCCN)nn1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NCCNC(=O)/C=C/C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (14 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (9 μl, 0.1 mmol) and the solution was stirred at room temperature for 5 minutes. This solution was added to a solution of N3-(2-aminoethyl)-N5,N5,1-trimethyl-1,2,4-triazole-3,5-diamine (18 mg, 0.1 mmol) and TEA (42 μl, 0.3 mmol) in a mixture of anhydrous dichloromethane (1 ml) and anhydrous DMF (1 ml) and the resulting mixture was stirred at room temperature. After one hour, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 5% to 100% acetonitrile) to yield 8 mg of a solid (0.026 mmol, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Cl)[CH2:11][CH2:12][CH3:13].O.Cl.CCOCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCC[Mg]Cl
Reactant: O=Cc1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 3-chlorobenzaldehyde (1.4 g, 10 mmol) in THF (10 mL) was cooled to −10° C., then 2.0 M n-butylmagnesium chloride (10 mL) was added. The reaction was allowed to warm to RT under N2 overnight. Next day the reaction was cooled to 0−5° C., water (5 mL) was added, followed by 2N HCl—Et2O partition. The organic layer was washed with brine, then dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography using 9/1 hex/EtOAc. Recovered 1.25 g (63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:23]([CH3:35])[CH:24]=[C:25]([NH:27]C(=O)OC(C)(C)C)[N:26]=2)=[C:20]2[C:15]([N:16]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:17](=[O:38])[N:18]([CH3:37])[C:19]2=[O:36])=[N:14]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:27][C:25]1[N:26]=[C:22]([C:21]2[N:13]([CH2:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[N:14]=[C:15]3[C:20]=2[C:19](=[O:36])[N:18]([CH3:37])[C:17](=[O:38])[N:16]3[CH2:39][CH:40]2[CH2:41][CH2:42]2)[N:23]([CH3:35])[CH:24]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(N)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was synthesized by treating tert-butyl 2-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-imidazol-4-ylcarbamate with 10% TFA in dichloromethane at room temperature for 5 hours. Mass: 491.26 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[CH2:27](I)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH2:27][CH2:28][CH2:29][CH3:30])=[S:25]
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Reactant: CCCCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCSC(=S)N1[C@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1C
Yield: 74.7 %

Procedure:
In the same manner as described in Example 34 by using (1S, 3S)-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (1.08 g), triethylamine (1.01 g), CS2 (0.76 g), n-butyl iodide (1.84 g) and dimethylformamide (8 ml), there is prepared the title compound (1.3 g, 75%) as colorless needles, m.p. 110°-113° C. (recrystallized from aqueous ethanol, [α]D20 +181.8° (c=1.0, methanol); NMR (CDCl3, δ): 0.97 (m, 3H, --(CH2)3CH3); Mass m/e: 348 (M+), 258 (M+ --C4H9SH).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17]>C(O)C.C(N(CC)CC)C>[C:16]([NH:20][C:21]([NH:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: N[C@@H](CO)Cc1cccc(C(=O)O)c1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc(C(=O)O)c1
Temperature: 60 °C

Procedure:
The process is performed as in Example 2, starting with 1.82 g of (2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride in 20 cm3 of ethanol, 4.2 cm3 of triethylamine and 1.7 cm3 of tert-butyl isothiocyanate. After heating for 21 hours at a temperature in the region of 60° C. and an identical work-up, 2.31 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea are obtained in the form of a light brown foam. (Rf=0.33 in a 12/6/1 by volume mixture of chloroform/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:34][CH2:33]1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: NC1CC1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC2CC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and cyclopropyl amine as starting materials. MS: m/z (MH+)=461.2
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.ClC(Cl)C>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Analogously to the instructions for example 7, 5 g (27.64 mmol) of 4-fluoro-3-(trifluoromethyl)-aniline in 25 ml of dry pyridine is reacted with 4.82 g (27.4 mmol) of chlorosulfonyl acetic acid methyl ester in 100 ml of dry dichloroethane. After crystallization from ether/hexane, 7.35 g=84.35% of the theoretical yield is obtained. Melting point 111°-112° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16](Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(O)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]([N:23]([CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2Br
Reactant: CNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2N(C)c1ccccc1
Reaction time: 8.5 h
Yield: 55.2 %

Procedure:
5.0 g. (0.016 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 50 ml. of ethanol. To the solution 3.5 ml. (0.032 mole) of N-methyl-aniline are added and the reaction mixture is boiled for 8-9 hours in a nitrogen gas atmosphere. 50 ml. or 5% by weight hydrochloric acid solution is then added to the solution and shaken out three times with 25 ml. of dichloromethane. The combined organic layers are dried above calcinated sodium sulfate and evaporated at reduced pressure. The residue is dark oil which crystallizes upon the addition of some methanol. 3.0 g. (55.2%) of 6-methyl-9-(N-methyl-anilino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are obtained. Melting point: 175°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH2:8][Br:10])[CH:7]=1
Reactant: BrBr
Reactant: Cc1cc(Br)ccc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr
Reaction time: 0.5 h

Procedure:
To a refluxing solution of 5-bromo-2-fluorotoluene (3.8 g, 20 mmol) in CCl4 (30 mL) illuminated with a 275 W UV-sun lamp, a solution of Br2 (1.1 mL, 20 mmol) in CCl4 (30 mL) was added dropwise. Refluxing and irradiation were continued for an additional 0.5 h and then the clear pale amber solution was concentrated. Distillation of the residue provided the desired compound (1a) as a clear colorless oil; bp 126°-136° C. (15 mm); NMR 4.38 (2H, s), 6.6-7.7 (3H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>C1(C)C=CC=CC=1>[CH3:5][C:6]1[C:7]([C:8]([Cl:3])=[O:9])=[CH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Temperature: 25 °C

Procedure:
Thionyl chloride (4.35 g, 36.5 mmol) was added to a mixture of 2-methyl-6-trifluoromethyl nicotinic acid (5.00 g, 24.4 mmol) in 75 mL of toluene and the mixture was heated at reflux for 3 hours. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. Excess thionyl chloride was removed by azeotrope with toluene. The resultant acid chloride was used as is in Example 4, Step B.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(#N)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)=[O:31])[CH3:34]
Reactant: Nc1ccc2ccc3cccc4ccc1c2c34
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCNc1ccc2ccc3cccc4ccc1c2c34

Procedure:
A mixture of 1-aminopyrene (5 g), potassium carbonate (15 g) and ethyl 6-bromohexanoate (10 g) in 60 mL acetonitrile was refluxed for 24 hours. The solvent was removed and the product was purified by a silica gel column eluting with EtOAc/hexane.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:30][C:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:12](=[O:11])[CH2:16][N:15]1[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1(C)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)CC1(C)c1ccccc1
Temperature: 0 °C

Procedure:
To a flame-dried flask equipped with stir bar under nitrogen was charged anhydrous CH2Cl2 (5 mL). The flask was immersed in a cooling bath at −78° C. Oxalyl chloride (0.24 mL, 2.7 mmol) was added neat followed by DMSO (0.29 mL, 4.1 mmol) dropwise. The reaction was stirred 10 minutes at −78° C. prior to the addition of alcohol 20-5 (0.19 g, 0.7 mmol) in minimal CH2Cl2. The resulting solution was stirred an additional 1 hour at −78° C. prior to the addition of Et3N (0.76 mL, 5.4 mmol) neat and dropwise. The reaction warmed to 0° C. over 2 hour. Upon completion, the reaction solution was washed with 5% aq. NaHCO3, dried (MgSO4), filtered and concentrated. The residue was carried crude into the vinyl triflate formation: LRMS m/z (M-C(CH3)3+H) 220.1 found, 220.2 required.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[CH:3]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].[CH2:16]1COC[CH2:17]1>CCOCC.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][N:2]1[C:6](/[C:7](=[N:15]/[S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])/[CH2:16][CH3:17])=[CH:5][N:4]=[CH:3]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cn1cncc1C=O
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Solvent: O
Product: CC/C(=N\S(=O)C(C)(C)C)c1cncn1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-3H-imidazole-4-carbaldehyde (1.40 g, 12.7 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (2.36 g, 19.1 mmol) and titanium (IV) isopropoxide (11.2 mL, 38.1 mmol) in THF (10 mL) was warmed at reflux for 18 hours. The mixture was cooled to room temperature, and diluted with ether (100 mL) and water (6 mL). The mixture was stirred for 10 minutes and then dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes, and concentrated to afford 2-methyl-propane-2-sulfinic acid [1-(3-methyl-3H-imidazol-4-yl)-prop-(E)-ylidene]-amide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:6]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(C)nc1Cl

Procedure:
Prepared in a similar manner to example 4 using 2-chloro-6-methylnicotinic acid and 4-Heptylamine. MS (M+H, 269).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][O:16]S(C)(=O)=O)[CH2:10]OC(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:21][CH2:10]1)[CH2:15][OH:16]
Reactant: CC(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OC[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
In 250 ml of toluene was dissolved 50 g of (S)-2-(2,4-difluorophenyl)-1-acetoxy-3-methanesulfonyloxy-2-propanol and thereto was added 250 ml of 20% aqueous solution of potassium hydroxide and then the resulting liquid was stirred at room temperature for 12 hours. A toluene-layer was separated and the aqueous layer was extracted three times with 100 ml of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and the solvent was removed The residue was purified by column chromatography on silica gel to give 21 g of (S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-propanol. The optical purity thereof was determined by HPLC analysis (column: CHIRALPAK AS made by Daicel Chemical Industries, Ltd., eluent: n-hexane/isopropanol=98/2, detection wavelength: 254 nm, flow rate: 1.2 ml/min).
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].OS(O)(=O)=O.C(O)(C)C>CC(C)=O.O>[Br:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]1=[O:13]
Reactant: CCOC(=O)C1CCC(Br)C(O)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC(Br)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-bromo-3-hydroxycyclohexanecarboxylate (15.06 g) in acetone (300 mL) at 0° C. was added CrO3 (12.0 g, 120 mmol), and 2 N H2SO4 (60 mL). The mixture was stirred at room temperature for 30 min. Isopropanol (15 mL) was added and the reaction was stirred for 20 min. The volume was reduced under vacuum then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, then brine, was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel (10% EtOAc in hexane) afforded 6.7 g of tide compound.
Reaction SMILES: O.NN.[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[Cl:32][C:33](Cl)(Cl)[C:34]#[N:35].Cl>CS(C)=O.[Cu]Cl>[Cl:32][C:33]([C:34]#[N:35])=[CH:4][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: N#CC(Cl)(Cl)Cl
Agent: Cl[Cu]
Agent: Cl
Agent: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=C(Cl)C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
To a solution of hydrazine hydrate diluted in 16 ml of dimethylsulfoxide under argon are added dropwise a solution of 4.76 g (16.41 mmol) of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate dissolved in 32 ml of dimethylsulfoxide. The reaction mixture is stirred at room temperature for 3 h before being cooled over an ice bath. Then, the successive addition is made of 11.45 ml (82 mmol) of triethylamine, 162 mg of copper (I) chloride and, in 5 min, a solution of 8.23 ml (82 mmol) of trichloroacetonitrile diluted in 16 ml of dimethylsulfoxide. The reaction mixture is stirred at room temperature for 18 h then poured onto an aqueous 0.1N hydrochloric acid solution. The product is extracted several times with dichloromethane. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 8:2) to yield 1.52 g (26%) of tert-butyl 4-(4-(2-chloro-2-cyanovinyl)phenyl)piperazine-1-carboxylate in the form of a yellow solid (mixture of the two isomers Z/E).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:25])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=C(C#N)[CH:20]=[CH:19][N:18]=3)[CH:16]=2)=[CH:4][CH:3]=1.[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:25])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[C:29]([C:28]([OH:26])=[O:30])[CH:20]=[CH:19][N:18]=3)[CH:16]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CN(CCc1cnn(-c2cc(C#N)ccn2)c1)Cc1ccc(F)cc1
Reactant: CCO
Agent: [Na+]
Product: CN(CCc1cnn(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Yield: 80 %

Procedure:
Charged 2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carbonitrile (270 mg, 0.8 mmol), NaOH aqueous (5M, 0.5 mL) and ethanol (10 mL) to a flask, the mixture was then heated to reflux for half an hour, cooled in an ice-water bath, adjusted PH to 3˜4, filtered, collected the solid and dried to give the title compound (226 mg, 80%). 1H NMR (400 MHz, DMSO-d6): 2.70 (3H, s), 3.01-3.06 (2H, m), 3.25-3.27 (1H, m), 3.31-3.39 (1H, m), 4.26-4.30 (1H, m), 4.44-4.48 (1H, m), 7.29-7.34 (2H, m), 7.64-7.68 (2H, m), 7.74-7.76 (1H, m), 7.81 (1H, s), 8.28 (1H, s), 8.61 (s, 1H), 8.64 (1H, J=5.2 Hz, d), 10.49 (1H, br). [M+H] Calc'd for C19H19FN4O2, 355; Found, 355.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1([CH2:27][OH:28])[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2([CH2:27][OH:28])[CH2:26][O:25][CH2:24]2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 10.9 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.23 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (267 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 30 mg of (3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)oxetan-3-yl)methanol as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[CH:17][C:9]2[O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:8]=2[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][C:12]1([CH3:16])[CH2:11][O:10][C:9]2[CH:17]=[CH:18][C:6]([CH2:4][OH:3])=[CH:7][C:8]=2[O:14][CH2:13]1
Reactant: CCOC(=O)c1ccc2c(c1)OCC(C)(C)CO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(CO)cc2OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
3,3-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid ethyl ester (30) (9.00 g) is dissolved in THF (150 ml) and a 1.5 M solution of diisobutylaluminium hydride in toluene (120 ml) is slowly added. The resulting reaction mixture is stirred 1 h at RT, then cooled to −30° C. and H2O (120 ml) is cautiously added. After letting the temperature rise to RT a 20% aq. HCl solution (100 ml) is added. The ether layer is collected, washed with H2O and dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, hexane/AcOEt 4:1) yields 7.25 g of (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31), MS (ESI) 208.1 (M•)+.