Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.[H-].[Na+].[F:15][CH2:16][CH2:17]I.O>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:16][CH2:17][O:12][CH2:11][C:5]1[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CO)cc(CO)c1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CO)cc(COCCF)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of 1 g of 5-methoxy-1,3-benzenedimethanol in 10 ml of DMF there was added 238 mg of sodium hydride (60% oily suspension) at 0° C. After stirring at room temperature for 30 minutes, 1.04 g of 1-fluoro-2-iodoethane was added and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (145 mg) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2Co3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143°-144° C.; 1H NMR (CD3OD, 400 MHz) β 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:22]3[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]=3[S:16][C:15]=2[CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][CH2:15][CH2:14][CH:22]([CH3:21])[CH3:17].[OH:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:22]3[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]=3[S:16][C:15]=2[CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Sc2c(Cc3cccc4ccccc34)sc3c2c(=O)n(C)c(=O)n3CC(C)C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(O)c3)c(Cc3cccc4ccccc34)sc21
Product: CCCC(C)C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Boron tribromide (1M solution in dichloromethane, 5.63 ml) was added to a stirred solution of 5-[(3-methoxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 26, 0.97 g) in anhydrous dichloromethane (50 ml) at 0° C. under nitrogen. After 1 hour, saturated sodium hydrogen carbonate solution (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate:isohexane (3:2) and then recrystallised from ethyl acetate:isohexane to give the title compound (0.468 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:14][N:15]([CH3:16])[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:13])[C:5]=1[N+:10]([O-:12])=[O:11])=[O:8]
Reactant: Cc1nn(C)c(C(=O)Cl)c1[N+](=O)[O-]
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nn(C)c(C(=O)N(C)C)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
A solution of 40 g of 1,3-dimethyl-4-nitropyrazole--5-carboxylic acid chloride in 50 ml of methylene chloride is added dropwise at from 10° to 20° C., while cooling, to 43 g of a 40% strength aqueous solution of dimethylamine; stirring is continued for a further 20 minutes. The resulting mixture is rendered alkaline with potassium carbonate; the organic layer is separated off, and the aqueous phase is extracted by shaking it with methylene chloride. The organic solution is dried and concentrated, and the residue is triturated with petroleum ether (bp 40° to 70° C.) to yield 38.3 g of N,N,1,3-tetramethyl-4-nitropyrazole-5-carboxamide, mp 57° to 59.5° C., which is converted into a product of mp 114° to 115.5° C. on recrystallization from cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:41](=O)[CH2:42]CCl)[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][N:35]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:30][CH:31]=3)[CH2:36][CH2:37]2)[N:3]=1
Reactant: CC(C)(C)c1ccc(N2CCN(C(=O)CCCl)CC2)cc1
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccc(C(C)(C)C)cc5)CC4)c3C2=O)cc1

Procedure:
A target compound (173.3 mg, 0.336 mmol, 86.8%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (94 mg, 0.388 mmol) with potassium carbonate (80.4 mg, 0.582 mmol) and 1-{4-(4-t-butylphenyl)piperazin-1-yl}-3-chloropropan-1-one (131.5 mg, 0.426 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([Cl:19])=[N:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:26][CH2:27][C:28](=[O:42])[CH2:29][CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:45](CC)CC)C.[C:50]1([CH3:59])[CH:55]=[CH:54][C:53]([C:56](Cl)=[O:57])=[CH:52][CH:51]=1>C(Cl)Cl>[NH2:31][CH2:30][CH2:29][C:28]1[N:45]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([CH3:59])=[CH:51][CH:52]=2)[N:26]([CH:20]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17](=[O:18])[C:16]3[C:11]([N:10]=2)=[N:12][C:13]([Cl:19])=[N:14][CH:15]=3)[CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:27]=1.[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([Cl:19])=[N:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:26]([CH2:27][C:28](=[O:42])[CH2:29][CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[C:56](=[O:57])[C:53]1[CH:54]=[CH:55][C:50]([CH3:59])=[CH:51][CH:52]=1)[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NCC(=O)CCN1C(=O)c2ccccc2C1=O)c1nc2nc(Cl)ncc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(c1nc2nc(Cl)ncc2c(=O)n1Cc1ccccc1)N(CC(=O)CCN1C(=O)c2ccccc2C1=O)C(=O)c1ccc(C)cc1
Product: CCC(CC)C(c1nc2nc(Cl)ncc2c(=O)n1Cc1ccccc1)n1cc(CCN)nc1-c1ccc(C)cc1

Procedure:
Formula 402 where R1 is H; R3 is Cl; R5 is Benzyl; R6 is Isopentyl; R6′ is H; Rc is p-Tolyl; W and Y are —C═; X and Z are —N═: A solution of 2-{4-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl)-2-ethyl-butyl-amino]-3-oxo-butyl}-isoindole-1,3-dione (1.58 g, 2.69 mmol), triethylamine (245 mg, 2.42 mmol), and p-toluoyl chloride (374 mg, 2,42 mmol) in methylene chloride (10 mL) is stirred at room temperature for 2.0 h. The reaction is washed sequentially with 0.5 N HCl, water, 5% NaHCO3, water and brine, and dried (Na2SO4). The filtrate is concentrated in vacuo and purified by flash chromatography (silica gel 3:2 hexanes:EtOAc as eluent) to provide the title compound, N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl)-2-ethyl-butyl]-N-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-oxo-butyl]-4-methyl-benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:29]=[CH:28][C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:27])[C:24](O)=[O:25])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1>C(OCC)C>[F:11][C:12]1[CH:29]=[CH:28][C:15]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:27])[C:24]([NH:1][C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[CH:4][CH:3]=3)=[O:25])[CH2:21][CH2:22]2)=[CH:14][CH:13]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2cn[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol (Aldrich) and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 162-164° C. (diethylether)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br.Br.[CH:15]12[CH2:21][CH:18]([NH:19][CH2:20]1)[CH2:17][NH:16]2.C1N2CCN(CC2)C1.C(Cl)Cl.CO>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:16]3[CH2:17][CH:18]4[CH2:21][CH:15]3[CH2:20][NH:19]4)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: C1NC2CNC1C2
Agent: Br
Agent: C1CN2CCN1CC2
Solvent: CCCCO
Solvent: ClCCl
Solvent: CO
Product: Clc1ccc2c(N3CC4CC3CN4)ccnc2c1

Procedure:
4,7-Dichloroquinoline (0.38 g, 1.9 mmol) and 2,5-diazanorbornane dihydrobromide (1.0 g, 3.8 mmol), and DABCO (1.3 g, 11.4 mmol) in n-butanol (20 mL) are reacted according to method B yielding the product after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]#[N:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:13][CH2:14][C:15](=[O:19])[CH2:16][CH:17]=[O:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:16]([CH:17]=[O:18])[C:15](=[O:19])[CH2:14][CH3:13])[CH:7]=[C:8]([C:11]#[N:12])[C:9]=1[OH:10]
Reactant: N#Cc1cc(C=O)cc(O)c1O
Reactant: CCC(=O)CC=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC(=O)C(C=O)=Cc1cc(O)c(O)c(C#N)c1

Procedure:
A mixture 1.6 g of 3,4-dihydroxy-5-cyanobenzaldehyde, 2.0 g of 3,5-pentanedione, 0.2 ml of piperidine and 0.6 ml of acetic acid in 70 ml of toluene was refluxed for 2 h with Dean-Stark separator. The solvent was evaporated in vacuo and the residue was crystallized from acetone-cyclohexane. mp 228°-232° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[3H][CH2:8][C:9](ON1C(=O)C2=CC=CC=C2C1=O)=[O:10].[CH3:23][I:24]>C(#N)C>[I-:24].[C:9]([O:6][CH2:5][CH2:4][N+:2]([CH3:23])([CH3:3])[CH3:1])(=[O:10])[CH3:8]
Reactant: CN(C)CCO
Reactant: [3H]CC(=O)ON1C(=O)c2ccccc2C1=O
Reactant: CI
Solvent: CC#N
Product: CC(=O)OCC[N+](C)(C)C
Product: [I-]
Temperature: 75 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylaminoethanol (4 μL, 0.04 mmole) was dissolved in dry acetonitrile (0.25 mL) and was placed in a reaction vessel connected to the vacuum line. N-tritioacetoxyphthalimide (0.04 mmole, specific activity 13 Ci/mmole) in dry acetonitrile (0.8 mL) was then added through the side-arm of the reaction vessel. The mixture was heated at 75° C. for 2 hours under N2, then brought to room temperature and methyl iodide (20 μL) was injected. The mixture was stirred for 1 hour. The solvent and excess of methyl iodide was evaporated under vacuum. Deuteriated water (0.5 mL) was added and removed. D2O (1 mL) was then added to the residue and filtered and the product was analyzed by 1H and 3H NMR spectroscopy.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH2:21]([S:20][CH2:19][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Reactant: ClCSCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CSCc1ccccc1)(CC(C)C)C(=O)OCC
Reaction time: 1 h
Yield: 98 %

Procedure:
Diethyl isobutylmalonate (22.0 g.) was added to a stirred suspension of sodium hydride (4.8 g. 50% dispersion in oil) in dry toluene (200 ml.), under nitrogen. The mixture was stirred at 80° for one hour. The mixture was cooled and benzyl chloromethyl thioether 5 (16.0 g.) in dry toluene (50 ml.) was added and the mixture was stirred at 80° for two hours. The mixture was cooled and poured into water. The aqueous mixture was extracted into diethyl ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzylthiomethyl-2-isobutylmalonate (32.0 g.) was obtained as a yellow oil and was used without further purification.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CO[C:31]1[C:35](OC)=[N:34][S:33](=[O:39])(=[O:38])[N:32]=1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][NH2:47])[CH:41]=1>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:31]2[C:35]([NH:47][CH2:46][C:42]3[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=3)=[N:34][S:33](=[O:39])(=[O:38])[N:32]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: NCc1cccnc1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2NCc2cccnc2)cs1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 7.0 g; 23 mmoles) in 180 ml of methanol was added dropwise to a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (4.1 g; 23 mmoles) in 400 ml of methanol at 8°. This was followed by 3-picolylamine (2.74 g; 25.3 mmoles) and the reaction mixture was stirred at 8° for 15 minutes and at ambient temperature for 20 hours. The reaction solution was evaporated and the residue flash chromatographed on 125 g of silica gel (230-400 mesh) using CH3CN(90):CH3OH(10):NH4OH(0.5) as the eluant. A second purification by preparative high pressure liquid chromatography on silica with CH2Cl2 (85):95%EtOH(15):NH4OH(0.5) as the mobile phase yielded 0.78 g of the title compound as a buff-colored foam containing 0.4 mole of ethanol, mp 128°-138° (foaming).
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:7][C@H:6]([O:8][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC[C@H](C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC[C@H](C)OS(C)(=O)=O
Temperature: 5 °C
Yield: 75.7 %

Procedure:
(S)-6-Methyl-hept-5-en-2-ol (2.64 g, 20.58 mmol) and DIEA (6.45 mL, 37.0 mmol) were dissolved in anhydrous DCM (28 mL), the reaction mixture was cooled to 5° C., mesyl chloride (1.91 mL, 24.7 mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to RT. After 18 h at RT the reaction mixture was diluted with DCM (100 mL), washed with water (3×35 mL), brine (35 mL), dried with MgSO4, solvent was concentrated to give a dark oil which was purified by SiO2 flash chromatography using Hexane-EtOAc to give the title compound as an oil (3.213 g, 76%). TLC, Hexane-DCM-EtOAc, 40:40:20, 2 Rf 0.70 (developed with KMnO4 stain). H1 NMR (CDCl3): • 5.08 (m, 1H), 4.80 (m, 1H), 2.99 (s, 3H), 2.10 (m, 2H), 1.75 (m, 1H), 1.69 (s, 3H), 1.62 (m, 1H), 1.61 (s, 3H), 1.43 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([OH:23])=O.S(Cl)(Cl)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:23]
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(C(=O)N4CCOCC4)c(OC)ccc3c2)c1
Temperature: 0 °C

Procedure:
2-Methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (200 mg, 0.65 mmol, 1 eq) is boiled under reflux with 5 ml of thionyl chloride under a nitrogen atmosphere for 30 min according to method E. The residue is dissolved in dry THF and added to 1 ml of morpholine cooled at 0° C. The reaction mixture is boiled under reflux over night. After the solvent has been removed on a rotary evaporator, purification is effected by column chromatography with dichloromethane/methanol 95/5 as the eluent. Characterization of the compound was not effected. The raw product was directly employed for ether cleavage.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[Br:13]N1C(=O)CCC1=O>C(Cl)Cl.C(OCC)(=O)C>[Br:13][CH2:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C)c1ccc[nH]1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Crude 2-[1-(trimethyl-silanyloxy)-vinyl]-1H-pyrrole was diluted with CH2Cl2 (10 ml), cooled to 0° C., and treated with N-bromosuccinimide (1.94 mmol, 0.35 g). The resulting mixture was put in a −20° C. freezer overnight. After warming to room temperature, the mixture was diluted with ethyl acetate (75 ml), washed with saturated aqueous sodium bicarbonate (2×20 ml), brine (2×20 ml), and the organics concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 0.29 g (80%) of 2-bromo-1-(1H-pyrrol-2-yl)-ethanone. 1H NMR (CDCl3) δ 7.12 (1H, dt, J=2.7, 1.3), 7.02 (1H, ddd, J=3.8, 2.4, 1.3), 6.36-6.31 (1H, m), 4.27 (2H, s).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:17]([N:19]([CH2:37][P:38]([OH:50])([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:39])[C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([N:19]([CH2:37][P:38]([O:50][CH2:15][O:14][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:39])[C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCN(CP(=O)(O)CCCCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CP(=O)(CCCCc1ccccc1)OCOC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of 1-[[ethyl[[hydroxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester in dimethylformamide under argon. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product is chromatographed to give 1-[[ethyl[[[(2,2-dimethyl-1-oxopropoxy) methoxy](4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].[NH:44]1[CH2:49][CH2:48][CH:47]([N:50]2[CH2:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[NH:52][C:51]2=[O:60])[CH2:46][CH2:45]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:32]([N:44]2[CH2:45][CH2:46][CH:47]([N:50]3[CH2:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[NH:52][C:51]3=[O:60])[CH2:48][CH2:49]2)=[O:33])[CH2:18][CH2:17]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 62.6 %

Procedure:
Triethylamine (50 μL, 0.356 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (60 mg, 0.143 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.25 mmol) in tetrahydrofuran (3 mL) at 0° C. After 25 min, the hydrochloride salt of 3-piperidin-4-yl-3,4-dihydroquinazolin-2(1H)-one (38 mg, 0.143 mmol) and dichloromethane (3 mL) were added and the mixture heated to 60° C. After 16 h, the reaction mixture was allowed to cool to ambient temperature and concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (54 mg). MS 604.2404 (M+1).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:21][N:20]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Yield: 79.7 %

Procedure:
Prepared according to Method D Step A from (2,3-difluorophenyl)-(4-methoxyphenyl)-methanone (1.1 g, 4.4 mmol), hydrazine hydrate (1.37 mL, 44 mmol) and DMAP (0.54 g, 4.4 mmol) to give the product (0.85 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:10]([NH:12][CH:13]([CH3:14])[CH3:15])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of methyl N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate (1.32 g) in methanol (15 ml) was added a solution of lithium hydroxide (294 mg) in water (15 ml). The reaction was rapidly stirred for 1.5 hours and then evaporated in vacuo. The residue was dissolved in water and neutralised using 2N hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo. The filtrate was applied to 4 Oasis cartridges (6 g), which were eluted with water (x2) and methanol (x2). The required fractions were combined and concentrated in vacuo to afford N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (1.01 g). HPLC Rt=2.51 minutes; m/z [M+H]+=343.