Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[C:12]([C:26]#[N:27])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([CH3:25])[O:17][C:15]=2[CH:16]=1)(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[C:12]([C:26]#[N:27])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([CH3:25])[O:17][C:15]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C#N)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1cc2c(cc1C#N)-c1ccncc1C(C)O2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
To a solution of tert-butyl((2S)-1-((9-cyano-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (15 mg, 0.034 mmol) in dichloromethane (2 mL) cooled to 0° C. was added HCl, 4M in dioxane (1.0 mL, 4.00 mmol) slowly over a period of 1 min. The reaction mixture was stirred at 0° C. for 5 min and then warmed to room temperature and allowed to stir for 2 h. The solvents were removed under reduced pressure and the crude material was washed with 5% methanol in ethyl acetate to afford 8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridine-9-carbonitrile (9 mg, 0.025 mmol, 73% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.74 (bs, 2 H), 8.58 (s, 1 H), 8.34 (d, J=6 Hz, 1 H), 7.01 (s, 1 H), 5.74 (t, J=6.4 Hz, 1 H), 4.48 (m, 1 H), 4.33 (m, 1 H), 3.78 (m, 1 H), 1.82-1.68 (m, 6 H), 1.06 (m, 6 H). LCMS (ESI) m/e 338.2 [(M+H)+, calcd for C20H24N3O2 338.2] LC/MS retention time (method D): tR=1.17 min. HPLC retention time (method A): tR=7.97 min and 8.03 min (diastereomeric mixture); HPLC retention time (method B): tR=8.77 min (peaks overlapped).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:27])/[CH:18]=[CH:19]/[CH2:20][N:21]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH3:22])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:27])/[CH:18]=[CH:19]/[CH2:20][N:21]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH3:22])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:3]=12
Reactant: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(I)c3c(N)ncnc32)C1)C1CCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)C1)C1CCC1
Temperature: 80 °C

Procedure:
A mixture of (R,E)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (22) (400 mg, 0.832 mmol), 4-chlorophenylboronic acid (156 mg, 1 mmol), K3PO4.3H2O (664 mg, 2.5 mmol) and Pd(dppf)2Cl2 (34 mg, 0.04 mmol) in DME/H2O (8 mL/2 mL) was purged with N2 (3×) and then heated to 80° C. overnight. After cooling down to rt, the reaction mixture was concentrated and the residue was purified by prep. HPLC (15%-95% acetonitrile/H2O (0.2% NH3H2O)) to provided (R,E)-1-(3-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin 1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (23) as a white solid. (20 mg, 5%), LC-MS (ESI): m/z (M+1) 466.1. 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.64 (m, 2H), 7.56 (m, 2H), 6.60 (m, 1H), 6.36 (dd, J=29.6, 15.6 Hz, 1H), 5.44 (m, 1H), 3.85 (m, 4H), 2.96 (dd, J=20.5, 6.3 Hz, 2H), 2.78 (m, 1H), 2.40 (m, 2H), 1.96 (m, 5H), 1.73 (m, J2H), 1.56 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][O:19][CH2:20][CH3:21].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][O:19][CH2:20][CH3:21])[N:4]([CH2:3][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])([CH3:22])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Yield: 54 %

Procedure:
1-(2-Amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine (111 mg, 0.355 mmol) was dissolved in 5 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (99 μL, 0.71 mmol) and methanesulfonyl chloride (28 μL, 0.36 mmol) and the reaction was allowed to warm to ambient temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (5 mL). The organic layer was separated and washed with H2O (2×5 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. Purification by column chromatography (SiO2, 2.5%-5% MeOH/CHCl3) gave N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (75 mg) as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:14]1)=[O:12]>C1COCC1>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[C:20]([CH2:19][N:16]2[CH2:15][CH2:14][N:13]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])=[O:12])[CH2:18][CH2:17]2)[CH:21]=1
Reactant: COC(=O)c1ccccc1NC(=O)N1CCN(Cc2cnc3ccccc3c2)CC1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1NC(=O)N1CCN(Cc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-[(4-quinolin-3-ylmethyl-piperazine-1-carbonyl)-amino]-benzoic acid methyl ester (26 mg) in THF (0.5 mL) under N2 was added potassium trimethyl silanoate (9 mg) in one portion and the mixture was stirred at rt for 14 h. The mixture was concentrated to give the title compound as a white amorphous solid (22 mg). 1H NMR (400 MHz, CD3OD): 8.81 (d, J=2.1 Hz, 1H), 8.23-8.21 (m, 1H), 8.14 (dd, J=8.4, 0.9 Hz, 1H), 7.96-7.93 (m, 1H), 7.91 (dd, J=7.9, 1.6 Hz, 1H), 7.88-7.85 (m, 1H), 7.68 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.54 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.19-7.23 (m, 1H), 6.81-6.85 (m, 1H), 3.71 (s, 2H), 3.51-3.54 (m, 4H), 2.49-2.51 (m, 4H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[O:14]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[B:21]([OH:24])[OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COB(OC)OC
Reactant: Brc1ccccc1COc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccccc1COc1ccccc1
Reaction time: 2 h

Procedure:
90 ml of n-butyllithium (1.6 M) in solution in hexane are added dropwise at −70° C. to 36 g of 1-bromo-2-(phenoxymethyl)benzene, obtained in step 1.1, in solution in 150 ml of tetrahydrofuran. After 2 hours at −70° C., 16 ml of trimethyl borate are introduced dropwise. The temperature of the reaction medium is allowed to rise to −30° C. The medium is hydrolysed with a saturated ammonium chloride solution, and then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulphate. After evaporation, 33 g of a white solid are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C@H:30]([C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)[CH3:31]>>[CH3:28][O:29][C@H:30]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CO[C@@H](C)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CO[C@@H](C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(C)=O)CC3)ccc2n1

Procedure:
1-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone from Example 148 (0.125 g) was reacted with (S)-2-(1-methoxyethyl)-1H-benzo[d]imidazole via General Procedure D to produce 22.1 mg of 164 following reverse phase HPLC purification. MS (Q1) 530.3 (M)+
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]([N:38]([CH3:39])[CH3:40])=[O:37])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)C[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CC(=O)N(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.95 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 69-2 (6.96 mmol, crude form) as starting materials, respectively 0.92 g (Isomer A: colorless powder) and 1.48 g (Isomer B: colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[CH:8]1.[CH3:16][C:17]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>ClCCl.CN(C1C=CN=CC=1)C>[Si:20]([O:13][CH2:12][C:10]1[N:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1cnc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cn(COCC[Si](C)(C)C)cn1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
1-(2-Trimethylsilylethoxymethyl)-1H-imidazole-4-methanol (100 g) was dissolved in dichloromethane (1 L), and under stirring TEA (122 mL), DMAP (5.35 g), and then TBDPSCl (149 mL) were added. After stirring for 1 day, the reaction mixture solution was washed with water, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=25%-50%) using silica gel column (product name: Ultra Pack E, manufactured by Yamazen Corporation) to afford the title compound (146 g).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[N:5][N:4]=[N:3]1.[OH-].[Na+].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.C(OCC)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[N:5][N:4]=[N:3]3)=[CH:18][CH:17]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCCCOc1ccc(-n2cnnn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(NCCCCOc1ccc(-n2cnnn2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.7 g of 4-[4-(1H-tetrazol-1-yl)phenoxy]butaneamine hydrochloride (Example 39) in 100 ml of water is treated successively with 3.5 ml of 10N NaOH and a solution of 2.7 g of 4-bromobenzenesulfonyl chloride in 100 ml of diethyl ether. The mixture is stirred at room temperature for 1.5 hours, the precipitate collected, washed with diethyl ether and water, and air dried. Recrystallization from ethanol gives the pure compound, m.p. 109°-110° C.; yield, 1.6 g.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:29])[C@@H:15]1[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>N1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:29])[C@@H:15]1[CH2:19][C@@H:18]([O:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][N:16]1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
540 Grams (2.84 moles) of technical p-toluenesulfonyl chloride were charged to a 5 liter flask. 1.5 Liters of anhydrous pyridine was added and the flask swirled to dissolve. Gradually, 600 g (2.40 moles) of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester were added and dissolved by swirling. The clear solution was maintained at room temperature and the conversion followed by TLC. After the starting material completely disappeared, the reaction mixture was transferred to a 12 liter beaker with an efficient agitator. 0.8 Liters of ice water and some tosylate seeds were added. Thick crystal slurry formed in about 10 minutes. Strong agitation was maintained and another 7 liters of an ice-water mixture were added over a period of one hour. The crystals were collected on a filter, the cake pressed down and washed with cold water until the effluent was free of chloride ions and suction applied to the cake until no more liquid emerged. The filtrate was discarded and the product dried to constant weight.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8]/[CH:9]=[CH:10]/[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:20]([Sn:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:10]=[CH:9]/[CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: C1COCCN1
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCC[Sn](/C=C/CN1CCOCC1)(CCCC)CCCC

Procedure:
A solution of morpholine (637 mg) and [(1E)-3-bromoprop-1-enyl](tributyl)stannane (1.00 g) in dry DMF (8.0 mL) was stirred for 24 h at 20° C. The reaction mixture was quenched with saturated Na2SO4(aq.). Extraction with Et2O and drying (MgSO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[H][H]>C(O)(=O)C.[Pt]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)s1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)s1

Procedure:
To a solution of EXAMPLE 34A (3.7 g) in acetic acid (200 mL) was added 5% platinum on carbon (370 mg). The mixture was shaken under 60 psi of hydrogen until all starting material was consumed, filtered and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The extract was washed with water and concentrated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([Cu])#[N:13]>CC(N(C)C)=O.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Stir the mixture of 1,4-dibromo-2-nitro-benzene (3.56 mmol)and CuCN (3.74 mmol) in DMA (4 ml) at 100° C. for 5hours. Cool to room temperature, dilute with EtOAc, filter through celite, wash the organic layer with brine, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (4:1 hexanes/EtOAc) to give 4-bromo-2-nitro-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](O)=[O:18]>>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([F:13])[CH:15]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: COc1ccc(C(=O)O)cc1F
Product: COc1ccc(C(=O)Nc2cc(OC)c(Cl)cc2OC)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step a, from 4-chloro-2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 197–199° C.; MS m/e 340 (M+H)+. Analysis for: C16H15ClFNO4 Calc'd: C, 56.56; H, 4.45; N, 4.12. Found: C, 56.33; H, 4.35; N, 4.05.
Reaction SMILES: O=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[S:29]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=S)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 14.1 mmol of diethyl 3-oxopentanedioate in 15 mL of toluene under argon add 49.4 mmol of sodium bicarbonate and 15.1 mmol of Lawesson's reagent. Stir for 1 h at room temperature then heat under reflux for 5 h. Cool, filter, and concentrate in vacuo. Purify the residue by silica gel chromatography using ethyl acetate/hexanes eluant to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=O.[CH3:13][N:14]=[C:15]=[S:16].C([O-])(O)=O.[Na+].Cl>CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:14]([CH3:13])[C:15](=[S:16])[NH:8][N:7]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Temperature: 70 °C

Procedure:
3,5-difluorobenzohydrazide (5 g, 29 mol) and methyl isothiocyanate (2.1 g, 29 mmol) were mixed in 2-propanol (100 ml) and heated to 70° C. o.n. The reaction was cooled to r.t. and the formed precipitate was filtered off. H2O (100 mL) and NaHCO3 (4 g, 48 mmol) were added to the solid and the mixture was heated to 70° C. for 2 h. The reaction mixture was cooled to r.t., acidified with concentrated HCl and the title compound, 6.4 g (97%), was collected by filtration. LC-MS (M++1): 228
Reaction SMILES: CS[C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>O1CCOCC1>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:22][N:21]([CH3:23])[CH2:20][C:18]1[O:19][C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:17]=1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 99.4 %

Procedure:
A solution of 1,1-bis(methylthio)-2-nitroethene (19.8 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (6.42 g) in dry dioxan (120 ml) was heated at 80° C. for 6 hours. Oxalic acid (3.8 g) in dry dioxan (40 ml) was added and the crystalline solid which separated was filtered, washed with dioxan and dried to give the title compound (12.55 g) m.p. 140°-143° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C3CC3)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C2CC2)c1
Yield: 68.7 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.132 g, 0.230 mmol) was dissolved in DCM (3 mL) and treated with TFA (3 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.0705 g, 0.158 mmol, 68.8% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.26 (br. s., 1H), 7.78 (s, 1H), 7.31-7.55 (m, 2H), 7.27 (br. s., 1H), 7.09 (s, 2H), 4.53 (d, J=1.39 Hz, 2H), 1.91-2.07 (m, 1H), 0.99 (m, 2H), 0.77 (m, 2H). LC-MS (ES−) m/z 443.18, 445.11 [M−1]. LC-MS (ES+) m/z 445.07, 447.08 [M+H].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1Cl)=O.[NH2:18][C:19](=[S:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:16][O:15][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:3]1[N:18]=[C:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[S:30][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCC(N)=S
Reactant: COc1ccc2ncc(Cl)c(C(=O)CBr)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2nccc(-c3csc(CCNC(=O)OC(C)(C)C)n3)c2n1

Procedure:
A mixture of bromomethylketone (b) (2.07 g, 9 mmol), 1,1-dimethylethyl (3-amino-3-thioxopropyl)carbamate (1.84 g, 9 mmol) and sodium bicarbonate (0.76 g, 9 mmol) in ethanol (120 mL) was heated to reflux for 1 hour under argon. The mixture was evaporated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic extract was washed with brine, dried and evaporated. The residue was chromatographed on silica eluting with a gradient of 0–50% ethyl acetate in dichloromethane affording a yellow solid (0.93 g, 26%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:6]23)[CH2:3][CH2:2]1.[H-].[Na+].C(OCC)(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH:1]1([CH2:4][N:5]2[C:6]3[C:7](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]([OH:10])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2=[O:12])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(CC2CC2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccccc2n(CC2CC2)c1=O

Procedure:
Reagents: Comp 20 (1.38 mmols, 0.3 g); Sodium hydride (2.91 mmols, 0.07 g); Diethyl malonate (6.91 mmols, 1.1 g).