Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:29][CH2:30][C:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:29][CH2:30][C:31]1([S:34]([NH:37][C:14]([C@@:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:16])(=[O:36])=[O:35])[CH2:33][CH2:32]1
Reactant: NS(=O)(=O)C1(CF)CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(CF)CC1
Temperature: 55 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (7.5 g, 33 mmol) in DMF (50 mL) was added CDI (10.69 g, 66 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by DBU (6 mL, 42.9 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ˜2 by using 1.5 N HCl solution. The precipitated solid was filtered and washed with water to get desired compound (11.5 g, 96%) as off-white solid. MS: MS m/z 361.4 (M+−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]#[CH:44])[CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:44]#[C:43][CH2:42][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[S:17][C:10]=12
Reactant: C#CCN1CCN(C)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 70.8 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A, 29.2 mg, 0.211 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.56), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (36 mg, 69%). HPLC: 100% purity (220 nm); LRMS (APCI+): 100% purity, 220 nm, m/z 602 (M+1) detected; 1H NMR (CDCl3, 400 MHz) δ 10.18 (s, 1H), 8.64 (s, 1H), 8.47 (d, J=5 Hz, 1H), 7.77 (m, 1H), 7.56 (s, 1H), 7.44 (m, 2H), 7.26 (m, 2H), 7.04 (m, 2H), 6.51 (d, J=5 Hz, 1H), 3.60 (s, 2H), 2.4-2.8 (m, 8H), 2.32 (s, 3H), 1.77 (m, 2H), 1.63 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:28])([F:29])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1

Procedure:
A mixture of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (264 mg, 656 μmol) and TFA (5.0 mL) was refluxed for 8 h under N2 atmosphere. The reaction mixture was concentrated in vacuo to afford crude to 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([NH:22]C=O)/[CH:5]=[C:6](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH2:7][P:8]([O:13]CC)([O:10]CC)=[O:9]>Cl>[NH2:22][CH:4](/[CH:5]=[C:6](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH2:7][P:8]([OH:13])([OH:10])=[O:9])[C:3]([OH:25])=[O:2]
Reactant: CCOP(=O)(C/C(=C/C(NC=O)C(=O)OC)c1ccccc1)OCC
Agent: Cl
Product: NC(/C=C(/CP(=O)(O)O)c1ccccc1)C(=O)O

Procedure:
0.15 g of E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid methyl ester are dissolved in 10 ml of 4.5N hydrochloric acid and heated at 75° for 192 hours. After concentration in vacuo, the foamy residue is dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide (1:1) is added dropwise thereto. The resulting white precipitate is filtered off and recrystallised from water/acetone (1:2). E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid is thus obtained inthe form of colourless needles, m.p. 230°-233°.
Reaction SMILES: OC1C(=O)NC=C(CCC2C=CC=CC=2C)C=1.C[O:19][C:20]1[C:25]([O:26]C)=[CH:24][C:23]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:22][N:21]=1>>[OH:26][C:25]1[C:20](=[O:19])[NH:21][CH:22]=[C:23]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH:24]=1
Reactant: COc1cc(C#Cc2ccc(C)cc2)cnc1OC
Agent: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Product: Cc1ccc(CCc2c[nH]c(=O)c(O)c2)cc1

Procedure:
Prepared as described for 3-hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (Example 27) from 2,3-dimethoxy-5-[(4-methylphenyl)ethynyl]pyridine (Intermediate 35).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[C:13]3[CH:20]([CH2:21][Cl:22])[CH2:19][N:18]([C:23]([O:25]C(C)(C)C)=O)[C:14]3=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)C1C=CC=CC=1.Cl.C(Cl)CCl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][C:46](C(O)=O)=[CH:45]2>C(OCC)(=O)C>[Cl:22][CH2:21][CH:20]1[C:13]2=[C:12]3[C:17](=[CH:16][CH:15]=[C:14]2[N:18]([C:23]([C:46]2[NH:47][C:48]4[C:44]([CH:45]=2)=[CH:43][C:42]([O:41][CH3:40])=[CH:50][CH:49]=4)=[O:25])[CH2:19]1)[NH:9][C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11]3
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCOC(=O)c1cc2c3c(ccc2n1C(=O)c1ccccc1)N(C(=O)OC(C)(C)C)CC3CCl
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)c1cc2cc(OC)ccc2[nH]1)CC3CCl
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
Compound 3.7(100 mg, 0.21 mmol) was treated with a solution of hydrochloric acid in ethyl acetate (4M, 500 μL). After 30 min, the solvent was concentrated and DMF (1 mL) was added. The solution was treated with EDC (120 mg, 0.63 mmol) and 5-methoxyindole-2-carboxylic acid (120 mg, 0.63 mmol). After 16 h, the solvent was removed under reduced pressure and the residue (the 6N-benzoyl protected precursor of compound 3.8) was dissolved in CH3OH (1 mL). A solution of NaOCH3 in CH3OH (2M, 100 μL) was then added and the solution stirred for 10 minutes. The solvent was removed and chromatography (SiO2, 10% ethyl acetate/hexanes) gave the product (3.8) (100 mg, 86%). FABMS (NBA/NaI) m/z 557 (M+H+ expected 557).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-].[Si](C=[N+]=[N-])(C)(C)C.N#N>CO>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: C=[N+]=[N-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Yield: 99 %

Procedure:
A 1 L flask was charged with 2,6-difluoro-3-nitrobenzoic acid (17.0 g, 83.7 mmol) and MeOH (170 mL, 0.5M). The flask was placed in a cold water bath, and an addition funnel charged with a 2M solution of trimethylsilyl (“TMS”) diazomethane in hexanes (209 mL, 419 mmol) was attached to the flask. The TMS diazomethane solution was added slowly to the reaction flask over the course of 2 hours. A large excess of reagent was required in order for the reaction to reach completion as determined by the ceased evolution of N2 upon further addition of reagent. The volatiles were removed in vacuo to afford methyl 2,6-difluoro-3-nitrobenzoate as a solid (18.2 g, 99%). The material was taken directly onto Step B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:17][OH:18]>C1C=CC=CC=1>[CH3:17][O:18][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][N:14]1[CH2:15][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][C:13]1=[O:16]
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC
Reactant: CO
Solvent: c1ccccc1
Product: COc1ccc(CN2CC(c3ccc(OC)c(OC)c3)CC2=O)cc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
30 g (0.136M) of the pyrrolidone (9) was treated with Triton B (60 ml of a 40% methanol solution in 400 ml of benzene. Benzene was distilled off in vacuo, and 400 ml of benzene was again added to the residue. This procedure was repeated three times, and 25.31 g of 3,4-dimethoxybenzyl chloride was added thereto at room temperature. The mixture was stirred at 60° C. for 6 hr, and water was added to the reaction mixture. The resultant organic phase was separated and washed twice with water and once with a saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo. The residue was recrystallized from ethanol to prepare 41.54 g (yield: 82%) of the intended product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[O:15]=[C:16]1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[NH:17]1>C(C#N)(C)=O>[C:24]([O:23][C:21]([N:20]1[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[C:16]1=[O:15])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2ccccc21
Reactant: Clc1ncnc(Cl)n1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)n1c(=O)n(-c2ncnc(Cl)n2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(4-Chloro-[1,3,5]triazin-2-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester was prepared by a process similar to that described by N. A. Meanwell, et al., J. Org Chem., 60,1565-82 (1995). A mixture of 2,4-dichloro-1,3,5-triazine (0.64, 4.26 mmol) and solid K2CO3 (0.6 g, 4.34 mmol) was suspended in AcCN (10 mL) under nitrogen at RT followed by addition of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (1.0 g, 4.26 mmol). The mixture was stirred at RT for 1.5 h. The mixture was poured onto ice/water and the white solid formed, was collected by suction filtration and dried under vacuum to give 3-(4-chloro-[1,3,5]triazin-2-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:16]([O:17][CH3:18])=[C:15]([N+:19]([O-])=O)[CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C(OCC)(=O)C.[Fe]>[NH2:19][C:15]1[CH:14]=[CH:13][C:3]([CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[C:2]([Cl:1])[C:16]=1[O:17][CH3:18]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1Cl)OCC
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(N)c(OC)c1Cl)OCC
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a solution of diethyl 2-chloro-3-methoxy-4-nitrobenzylphosphonate (Compound 54F, 1 g, 2.96 mmol) in ethanol (15 mL), and iron powder (1.63 g, 29.6 mmol) was added aqueous 2N HCl (5 mL). The reaction mixture was heated to reflux for 1.5 h. The reaction mixture was cooled to RT and saturated solution of Na2CO3 was added until the pH was 9. The reaction mixture was filtered through celite and concentrated to give the residue. It was dissolved in ethyl acetate (25 mL) and washed with water, dried over sodium sulfate, filtered and concentrated to give the required product (89%, 900 mg). 1H NMR (300 MHz, CDCl3) δ 7.01 (d, 1H), 6.62 (d, 1H), 4.00-4.19 (m, 4H), 3.83 (s, 3H), 3.25 (d, 2H), 1.23 (t, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=O.[NH2:24][OH:25].Cl>>[CH:1](=[N:24][OH:25])[C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Reactant: NO
Agent: Cl
Product: ON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Yield: 76.1 %

Procedure:
was synthesized as described in Example 22 using (62) (150 mg, 0.50 mmol) instead of (55) and NH2OH.HCl (100 mg, 1.5 mmol). The reaction gave (63) (120 mg, 76%).Mp. 220-221° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH2:15])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[C:23](Cl)=[O:24]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH:15][C:23](=[O:24])[C:22]3[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:20]([O:19][CH3:18])[CH:21]=3)[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(sc(N)c2C#N)C1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: CCOC(=O)N1CCc2c(sc(NC(=O)c3cc(OC)cc(OC)c3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid ethyl ester (compound A1) and 3,5-dimethoxy benzoyl chloride.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][CH:6]=1)[CH:2]=[CH2:3].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:10][C:9]1[C:5]2[S:4][CH2:1][CH2:2][CH2:3][C:6]=2[S:7][CH:8]=1
Reactant: C=CCSc1cscc1Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Brc1csc2c1SCCC2
Yield: 89 %

Procedure:
A solution of 30.2 g (0.13 mol) of 3-allylthio-4-bromothiophene and 10.3 mls (0.13 mol) of pyridine in 250 mls of toluene was refluxed for 68 hours, cooled, washed with 1N HCl solution, 1N NaOH solution, water and brine and dried over MgSO4 and concentrated to give 27.2 g of an amber oil. The oil was chromatographed on 500 g of SiO2 eluting with hexane to give 16.2 g of the desired product as a colorless oil (90% purity).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a suspension of Example 5B (20 g, 41.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.85 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium(O) (4.84 g, 4.19 mmol) in N,N-dimethylformamide (500 mL) was added a solution of sodium bicarbonate (7.04 g, 84 mmol) in water (40 mL) and the mixture was stirred at 80° C. for 12 hours. Saturated aqueous sodium thiosulfate, water and ethyl acetate were added and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to provide the title compound. MS (CI) m/z 532 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CO[N:13](C)[C:14]([CH:16]1[CH:21]2[CH2:22][CH:18]([CH2:19][CH2:20]2)[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.Cl.[C:32]([S:36](N)=[O:37])([CH3:35])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.C(OCC)C.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C(OCC)(=O)C.C1COCC1.CCCCCC>[C:32]([S:36](/[N:13]=[CH:14]/[CH:16]1[CH:21]2[CH2:22][CH:18]([CH2:19][CH2:20]2)[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:37])([CH3:35])([CH3:34])[CH3:33]
Reactant: CON(C)C(=O)C1C2CCC(C2)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC(C)C[Al+]CC(C)C
Agent: CC[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1/C=N/S(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Diisobutylaluminium hydride (50 mL of a 1M solution in toluene, 50 mmol) was added to a pre-cooled (−78° C.) solution of tert-butyl 3-{[methoxy(methyl)amino]-carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate (6.17 g, 21.7 mmol) in diethyl ether (80 mL). The mixture was stirred at −78° C. for 2 hours and then at 0° C. for 10 min. The reaction was poured into a mixture of 1N hydrochloric acid (180 mL), diethyl ether (150 mL) and hexane (150 mL) and stirred for 20 min. The organic layer was washed with brine, dried Na2SO4) and concentrated. The residue was treated with THF (90 mL), tert-butylsulphinamide (3.15 g, 26 mmol) and titanium ethoxide (9.1 mL, 43.4 mmol) and stirred at ambient temperature for 12 h. The mixture was treated with brine (120 mL) and ethyl acetate (150 mL) and stirred for 30 min. The organic phase was removed and retained. The aqueous residue was washed with 2 further portions of ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on a pad of silica gel eluting with iso-hexane containing 0.5% triethylamine on a gradient of ethyl acetate (0-40%) to give the title product (6.1 g, 85%). 1H NMR (400 MHz, CDCl3): δ 7.94-7.88 (1H, m), 4.33 (0.5H, s), 4.22 (0.5H, s), 4.10 (0.5H, m), 4.02 (0.5H, m), 2.75-2.65 (1.5H, m), 2.58 (0.5H, d, J=5.5), 1.88-1.50 (4H, m), 1.48-1.38 (9H, m), 1.34-1.26 (2H, m), 1.24-1.20 (9H, m).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:12]([C:5]1([CH2:4][CH2:3][OH:2])[CH2:10][CH2:9][CH:8]=[CH:7][CH:6]1[OH:11])[CH3:13]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC1(CCO)CCC=CC1O
Yield: 103 %

Procedure:
A solution of 1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (5.00 g, 25.48 mmol) in 10 mL of anhydrous ether was added dropwise under nitrogen to a 0° C. solution of lithium aluminum hydride (967 mg, 25.48 mmol) in 25 mL of anhydrous ether. The reaction was quenched by dropwise addition of 0.97 mL of water, 0.97 mL of 1M NaOH (aqueous) and 2.7 mL of water. The solution was filtered and the salts were boiled 3× in 25 mL of ethyl acetate and these washings were combined with the first filtrate. The filtrate was concentrated in vacuo to afford 4.47 g (103%) of product as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC(C)C)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2) was alkylated with 2-iodopropane/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(4-isopropoxy-phenyl)-2-methoxy-acetamide as a colorless solid. MS 339.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1)[C:6]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]1)=[N:5]2.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[C:6]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:26]3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([N:1]=[CH:32][N:33]([CH3:35])[CH3:34])[CH:3]=3)[N:8]=2)[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: CCCN1CCN(c2nc3ccc(N)cc3nc2N2CCN(CCC)CC2)CC1
Reactant: COC(OC)N(C)C
Product: CCCN1CCN(c2nc3ccc(N=CN(C)C)cc3nc2N2CCN(CCC)CC2)CC1
Temperature: 64 °C

Procedure:
A 6.0 g. portion of 6-amino-2,3-bis(4-propyl-1-piperazinyl)quinoxaline (prepared as in Example 5) is mixed with 3.42 ml. of dimethylformamide dimethylacetal in a reaction flask fitted with a reflux condenser. The mixture is refluxed in an oil bath at 64° C. for three hours. The condenser is removed and the distillate is allowed to boil off as the oil bath is permitted to cool overnight. The flask is stripped of solvent by water pump evacuation and the residue is dissolved in 50 ml. of acetonitrile; is treated with activated charcoal and filtered. The filtrate is cooled at -10° C. causing separation of an oil. The supernatant is decanted and the oil is air dried to yield a crystalline solid which is recrystallized from 20 ml. of hexane by cooling at -10° C. The precipitate is filtered and is air dried to give the product of the example as a yellow solid, m.p. 95.5°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([O:10][CH3:11])=[CH:4][C:3]=1F.[CH3:13][S-:14].[Na+].Cl>CN(C)C=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([S:14][CH3:13])[C:2]([F:1])=[CH:7][C:6]=1[OH:8]
Reactant: COc1cc(F)c(F)cc1OC
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(SC)c(F)cc1O
Temperature: 25 °C

Procedure:
To a solution of 1,2-difluoro-4,5-dimethoxybenzene (2.61 g, 15 mmol) in N,N-dimethylformamide (20 ml) was added sodium thiomethoxide (95%, 1.11 g, 15 mmol). The reaction was allowed to reflux for 3 hours and then was cooled to room temperature. The mixture was poured into 200 ml ice-water and neutralized with 2 N HCl. The aqueous layer was extracted with ethyl ether (2×100 ml), washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford a mixture of the two title products.
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])([CH3:3])[CH3:2].C([Li])(CC)C.[Cl-].[NH4+].[O:26]1CCC[CH2:27]1>>[CH3:12][C:8]1[O:9][C:10]([CH:27]=[O:26])=[CH:11][C:7]=1[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17]
Reactant: Cc1occc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Product: Cc1oc(C=O)cc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10 g) in tetrahydrofuran (250 mL) was cooled to −78° C. with stirring, and then sec-butyllithium (1.3 M in cyclohexane; 37.25 mL) was added drop-wise over 10 mins. After stirring for 45 mins at −78° C., the cooling bath was removed for a period of 15 mins then re-introduced. A solution of N,N-dimethylformamide (14.4 mL) in tetrahydrofuran (25 mL) was added drop-wise and the resulting reaction mixture was stirred at −78° C. for a further 2 hours. The reaction mixture was allowed to warm to room temperature and then poured into saturated ammonium chloride solution (150 mL). This mixture was extracted with diethyl ether (2×350 mL), and the combined organic extracts were washed with water (500 mL) and brine (500 mL), dried, and concentrated in vacuo to give compound 33 as an amber coloured oil. LC/MS System A: Rt=4.86 mins.