Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1C(=O)O
Yield: 86.5 %

Procedure:
2-Amino-5-bromobenzoic acid (4.0 g, 0.018 mol) was dissolved in DMF (90 mL) and treated with carbonic acid di-tert-butyl ester (4.44 g, 0.020 mol), 4-dimethylamino-pyridine (0.219 g, 0.0018 mol) and triethylamine (2.8 mL, 0.020 mol) for 16 h at 70° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, then twice with 1 N hydrochloric acid, dried over sodium sulfate. The organic layers were concentrated to afford 5-bromo-2-tert-butoxycarbonylamino-benzoic acid as a yellow solid (4.92 g, 86.7%). 1H NMR (500 MHz, DMSO-d6) δ 1.46 (s, 9H), 7.72 (dd, J=2.5, J=8.5 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 10.44 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[CH2:16][CH3:17])[CH3:14].ClCCl>O1CCOCC1>[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:23]=[CH:24][CH:25]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCN(CC)Cc1cccc(N)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C
Yield: 11.2 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 3-((diethylamino)methyl)aniline (148 mg, 0.829 mmol). The mixture was heated in microwave for 140 minutes at 120° C. Dichloromethane was added, and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting solution was prepared by TLC (10% MeOH/DCM) to yield 10 mg 5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (11% yield). LCMS (M+1=324)
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:26][C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH2:11][CH2:10][C:9]=2[CH:27]=1)(=O)C.Cl.[OH-:29].[Na+]>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:26][C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[CH2:11][C:10](=[O:29])[C:9]=2[CH:27]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC1(CCN(Cc3ccc(N)cc3)CC1)O2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(CN2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)cc1
Yield: 88 %

Procedure:
A solution of 3,4-dihydro-6-acetamido-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine](136 mg, 0.36 mmol) and hydrochloric acid (6N solution, 13. 6 ml) in methanol (13.6 ml) was heated at reflux temperature for 1 hr. The reaction mixture was cooled to 0° C. and basified with 20% sodium hydroxide solution. Extraction with methylene chloride, drying and solvent evaporation gave 3,4-dihydro-6-amino-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (107 mg, 88%);
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2.[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:40](F)[CH:39]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]>CS(C)=O.O>[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:39]=[CH:40][C:41]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[C:49]([NH:16][CH:11]5[CH2:10][CH:9]6[N:8]([CH3:7])[CH:13]([CH2:14][CH2:15]6)[CH2:12]5)[CH:50]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CN1C2CCC1CC(N)C2
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1C2CCC1CC(Nc1cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc1C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Yield: 27 %

Procedure:
0.89 g of potassium carbonate and 6 g of 8-methyl-8-azabicyclo[3.2.1]octan-3-amine are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 100° C. for 1 hour and 40 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (92/8 as mixtures), so as to give 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzoate in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([CH2:19][O:9][C:5]2[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][CH:6]=2)[CH2:22][CH2:21]1
Reactant: ClCC1CC1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NCc1cccc(OCC2CC2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3-Cyanophenol (12.4 g) was dissolved in N,N-dimethylformamide (hereinafter, referred to as DMF; 100 mL). To the solution, potassium carbonate (30.5 g), potassium iodide (1.74 g), and (chloromethyl)cyclopropane (10.2 mL) were added, and the mixture was stirred at 90° C. for 4 hours. To the reaction mixture, water (130 mL) was added, and the resultant mixture was then extracted with toluene (130 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (hereinafter, referred to as THF; 60 mL). To the solution, a solution of lithium aluminum hydride (hereinafter, referred to as LAH) in THF (2.4 M, 68 mL) was gradually added dropwise at 0° C., and the reaction mixture was then stirred at 45° C. for 4 hours. To the reaction mixture, water (10 mL), an aqueous sodium hydroxide solution (1.0 M, 10 mL), and water (5.0 mL) were gradually added at 0° C. The resultant precipitate was removed by filtration and washed with 10% methanol/THF (400 mL). Then, the combined filtrate was concentrated under reduced pressure. To the residue, water (50 mL) was added, and the resultant mixture was then extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (18.1 g) as a crude product.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[C:42]2[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:44](=[O:49])[O:45][C:46]([CH3:48])([CH3:47])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:47][C:46]1([CH3:48])[O:45][C:44](=[O:49])[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:55])[CH3:56])[C:42]2[C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC1(C)OC(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)OC3(C)C)cc1

Procedure:
Analogously to Method D, 0.30 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.28 g of 8-bromomethyl-4,4-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (1:1 EtOAc-heptane); Rt=6.68.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Br)(Br)[Br:13].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[Br:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cnc1Br
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A sample of 3-methyl-5-nitropyridin-2-ol (1.44 g, 9.34 mmol) was placed in 35 mL pressure vessel and dissolved in a mixture of toluene/DMF (10:1 ratio; 15 mL). The vessel was capped with a septum, flushed with Argon and phosphorous tribromide (1.32 mL, 14.0 mmol) was added by syringe. The septum cap was replaced by a Teflon cap and the mixture was stirred for 20 min at 120° C. The mixture was cooled to room temperature, neutralized with a 3M NaOH solution and extracted with toluene (3×). The combined organic phases were dried over anhydrous MgSO4 and concentrated under vacuum to give 2.00 g of the desired 2-bromo-3-methyl-5-nitropyridine product as an orange solid (99%).
Reaction SMILES: [C:1]([C:4]1([O:9]/[N:10]=[C:11](/[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)\[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=O.Cl.[O:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1/[C:11](=[N:10]/[O:9][C:4]1([C:1](=[O:3])[NH:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1)/[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C(=N\OC1(C(=O)O)CCCC1)c1ccco1
Reactant: NOc1ccccc1
Agent: Cl
Product: COC(=O)/C(=N\OC1(C(=O)NOc2ccccc2)CCCC1)c1ccco1
Yield: 44 %

Procedure:
This compound prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and phenoxyamine hydrochloride as described in Preparation 7(c), was purified by chromatography on silica gel plates in ethyl acetate-light petroleum b.p. 40°-60° (3:1 v/v). τ(DMSO d6) 2.5-3.1 (phenyl), 7.7-8.1, 8.1-8.5 (cyclopentyl), 2.0, 3.28, 3.02 (furyl), 6.03 (methyl). Yield 44%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-c5nnn[nH]5)cc4)ncnc32)CC1
Yield: 12.7 %

Procedure:
4-{4-[4-(1H-Tetrazol-5-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (5.3 mg, 13%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 5-(4-hydroxyphenyl)tetrazole (Biofine International Inc., Blaine, Wash., USA; 15 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([CH:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]2[CH2:14]1)([O:11][CH3:12])=[O:10].IC>C1COCC1>[CH:35]1([C:24]2[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]3[CH2:14][C:13]([C:9]([O:11][CH3:12])=[O:10])([CH3:2])[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=23)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)OC)Cc1ccccc1-3
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of LDA in THF (1.2 mL of 0.5 N, 0.60 mmol) was added to a solution of methyl (±)-6-carbomethoxy-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (160 mg, 0.37 mmol) in THF (5 mL) at −78° C. Stirring was continued at −78° C. for 15 min when the mixture was slowly warmed to −50° C. Iodomethane (35 μL, 0.56 mmol) was added and the mixture was slowly warmed to −10° C. Stirring was continued for 30 min. The solution was quenched with MeOH. The solution was extracted with ethyl acetate and the extract washed with dilute HCl (2×), brine (3×), and then dried (Na2SO4). The extract was concentrated and the crude product purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (140 mg, 85%). ESI-MS m/z 446 (MH+) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19-1.33 (m, 3 H) 1.31-1.52 (m, 3 H) 1.63-1.84 (m, 3 H) 1.87-2.15 (m, 4 H) 2.34 (d, J=13.73 Hz, 0.4 H) 2.70 (d, J=13.73 Hz, 0.6 H) 2.88-3.12 (m, 2 H) 3.21 (d, J=13.73 Hz, 0.4 H) 3.33 (d, J=14.65 Hz, 0.6 H) 3.75 (d, J=10.68 Hz, 3 H) 3.95 (s, 3 H) 4.34 (d, J=14.65 Hz, 0.4 H) 4.87 (d, J=14.65 Hz, 0.6 H) 7.30-7.48 (m, 4 H) 7.69-7.79 (m, 1 H) 7.82-7.92 (m, 1 H) 8.11 (s, 0.4 H) 8.22 (s, 0.6 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:17][CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:17][CH3:18])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCBr
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc2cc(OCC)ccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-Hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) (8 g, 39 mmol) is dissolved in 80 ml of DMF and after addition of bromoethane (5.8 ml, 78 mmol) and Cs2CO3 (15.2 g, 46.6 mmol) the mixture is stirred for 2 h at 100° C. After evaporation of the mixture at high vacuum, the residue is dissolved in ethyl acetate, washed with water and with brine, dried over sodium sulfate and evaporated under reduced pressure. The yellow solid is used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.O1CCCC1.[C:15](Cl)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>[OH-].[Na+]>[C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C

Procedure:
29 g of L-valine is dissolved in 250 ml of 1N aqueous NaOH, and to the solution is added water so that 400 ml of the solution is obtained. To the solution is added 150 ml of tetrahydrofuran. Then, while vigorously stirring at 10° C., to the solution are added 100 ml of Boc-Cl by 1/5 amounts at intervals of ten minutes, while 2N aqueous NaOH is added after every addition of Boc-Cl in such amount as will provide a pH value of about 8 to 9. Two hours later, the mixture is extracted with diethyl ether. The aqueous layer is acidified with an aqueous solution of 0.5 M aqueous citric acid, whereby an oily substance is precipitated. The precipitate is extracted with ethyl acetate. The extract is washed with a small amount of water, dried over Na2SP4, and concentrated under reduced pressure. To the concentrated extract is added petroleum ether, and the mixture is allowed to stand in a refrigerator, whereby a crystal is formed. The crystal is filtered off and dried. Thus, there is obtained 30 g of Boc-valine having a melting point of 78° C. The yield of the product is 55%.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:16][CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH3:1][S:2][C:4]([S:16][CH3:17])=[C:5]([Cl:27])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSC(=Cc1ccc(CC(C)C)cc1)S(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSC(SC)=C(Cl)c1ccc(CC(C)C)cc1
Yield: 83.8 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(p-isobutylphenyl)ethylene (701 mg) was dissolved in 2 ml of chloroform, and 0.50 ml of triethylamine was added. With stirring under ice cooling, 5 ml of a chloroform solution of 380 mg of thionyl chloride was added over the course of 10 minutes. The mixture was further stirred for 30 minutes under ice cooling, and chloroform was added in an amount sufficient to adjust the total amount of the mixture to 30 ml. The mixture was then washed twice with 10 ml of water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a Florisil (chromatographic magnesium silicate) column using benzene as an eluent to afford 628 mg of 1,1-bis(methylthio)-2-chloro-2-(p-isobutylphenyl) ethylene as a colorless oil in a yield of 84%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH:11]=[C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1.CO>[Pt](=O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1
Reactant: C1=C(c2nccs2)CNC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1csc(C2CCNC2)n1
Reaction time: 3 h

Procedure:
To a solution of 2-(2,5-dihydro-1H-pyrrol-3-yl)-1,3-thiazole trifluoroacetate (2.49 g, 0.00936 mol) in methanol (100.0 mL, 2.469 mol) was added platinum dioxide (320 mg, 0.0014 mol) and the resulting mixture was hydrogenated on par shaker at 56 psi for 3 h. After filtration, the filtrate was concentrated in vacuo and dried under high vacuum to give the desired product as a solid. LC-MS (M+H) 155.2 (base).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.O>CN(C=O)C>[CH2:7]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][OH:15])[CH2:18][CH2:19]1)=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCC(CO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(CO)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (2.61 g, 18.9 mmol) and benzyl bromide (2.24 mL, 18.9 mmol) were added to a solution of 4-hydroxymethyl-cyclohexanecarboxylic acid (cis-trans=2.9:1 mixture) (2.49 g, 15.7 mmol) in DMF (31.5 mL) at room temperature, and the mixture was stirred at 60° C. for one hour. The reaction solution was cooled, and H2O (60 mL) was then added to the reaction solution, followed by extraction with hexane:ethyl acetate (2:1) (300 mL) twice. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (cis-trans=3.5:1 mixture) as a colorless oily substance (3.79 g, 97%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 55.8 %

Procedure:
A mixture of 0.5 g (0.0017 mole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292b) and 0.35 g (0.002 mole) of 4-amino-3-methoxy-benzoic acid in 20 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with 0.5M hydrochloric acid and water and dried to give 0.40 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8](=[O:12])[CH2:9][O:10][CH3:11])=[CH:13][CH:14]=1
Reactant: COCC(O)COc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
Dissolve 1-(4-fluorophenoxy)-3-methoxy-propan-2-ol (2.6 g, 12.99 mmol) in DCM (26 mL) and add molecular sieves, pyridinium chlorochromate (7.14 g, 32.47 mmol), and pyridine (5.25 mL, 64.93 mmol). Stir the mixture at ambient temperature overnight. Filter the mixture through a Celite® plug and wash the plug with Et2O. Concentrate the filtrate; then purify via flash column chromatography using 25% EtOAc in hexanes to provide the product as a clear oil (872 mg, 33.9%). MS (m/z): 216 (M+NH4).