Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[C:30]([S:31]([CH:34]([CH3:35])[CH3:36])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(=O)(=O)C(C)C)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][NH:10]1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:32][C:31]([F:33])([F:34])[C:30]([C:27]1[CH:26]=[CH:25][C:24]([N:10]2[CH2:11][CH2:12][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)(=[O:17])=[O:16])[CH2:14][C@@H:9]2[CH2:8][N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:29][CH:28]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2nccs2)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2nccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 6.1 %

Procedure:
A 20-mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg, 0.61 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (326 mg, 1.21 mmol, Example 27, Step 1), sodium tert-butoxide (175 mg, 1.82 mmol), Pd2(dba)3 (55.5 mg, 0.061 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (42.4 mg, 0.091 mmol, Strem Chemicals, Newburyport, Mass.) and toluene (5 mL). the vial was sealed and heated to 100° C. for 3 h. The reaction was filtered, concentrated and purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) that was a mixture of two isomers.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][S:14]/[C:15](/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16]\[C:17]([O:19]C)=O)=[CH:11][CH:10]=1>C1COCC1>[OH:19][C:17]1[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:14][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:28][CH:27]=1
Reactant: COC(=O)/C=C(\SCc1ccc(OC)cc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2sc(-c3ccccc3)cc2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (2.11 g, 18.8 mmol) was dissolved in 30 mL of THF at 25° C. A solution of crude methyl Z-3-(4'-methoxybenzylthio)-3-phenyl-2-propenoate (2.00 g, 6.36 mmol) in 10 mL of THF was added over 5-10 minutes. An additional 2×2 mL of THF was used to rinse the starting material into the reaction. After stirring an additional 1 hour at 25° C., the reaction was quenched with 1.5 mL of glacial acetic acid and poured into 100 mL of ethyl acetate. After washing successively with 50 mL of saturated aqueous sodium chloride, 15 mL of 2N ag. hydrochloric acid, and 50 mL of saturated ag. sodium chloride, the solution was dried over sodium sulfate, decanted, and evaporated. The residue was dissolved in dichloromethane and evaporated onto 10 g of silica gel. Flash column chromatography on 60 g of silica gel eluted with 1 L of 10% ethyl acete in hexane followed by 500 mL of 12% ethyl acetate in hexane gave 3-hydroxy-2-(4'-methoxyphenyl)-5-phenylthiophene as 0.35 g of off-white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.S(=O)(=O)(O)[O-].[Na+]>C(#N)C>[Br:12][C:8]1[C:7]([CH3:11])=[C:3]([C:2]([OH:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(O)c1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Br)ccc(O)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Step 2 A suspension of 2-hydroxy-6-methylbenzoic acid (1.32 g, 8.68 mmol) in acetonitrile (20 mL) at −20° C. was treated with tetrafluoroboric acid dimethyl ether complex (1.109 mL, 9.11 mmol), followed by portionwise addition of N-bromosuccinimide (1.699 g, 9.54 mmol) over 30 min. The mixture was warmed to 0° C. and stirred for 1 h, then was treated with 40% aqueous sodium bisulfate (10 mL). The acetonitrile was removed under vacuum and the aqueous residue was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water and brine, dried and concentrated to give 3-bromo-6-hydroxy-2-methylbenzoic acid as a white solid (1.60 g, 80%). 1H NMR (400 MHz, methanol-d4) δ 7.47 (1H, d, J=8.80 Hz), 6.67 (1H, d, J=8.80 Hz), 2.50 (3H, s). Mass spectrum m/z 231, 233 (M-1-1)−.
Reaction SMILES: [I-:1].[Na+].[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:37])[C@H:12]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[CH:13]2[CH2:15][CH2:14]2)[CH2:7][CH2:6]1)#[N:4].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:37])[C@H:12]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([I:1])[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[CH:13]2[CH2:15][CH2:14]2)[CH2:7][CH2:6]1)#[N:4]
Reactant: [I-]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(I)cnc21
Temperature: 110 °C
Yield: 79.1 %

Procedure:
In a 5 mL microwave vial were placed copper(I) iodide (5 mg, 0.027 mmol), sodium iodide (120 mg, 0.80 mmol), 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (150 mg, 0.27 mmol), 1,4-dioxane (1 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (8 mg, 0.054 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 20 h. The reaction mixture was cooled to room temperature and quenched with sat'd aqueous NH4OH (3 mL) then diluted with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 80% EtOAc/hexanes to isolate 130 mg (80%) of 2-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as an orange foamy solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[CH3:29][C:18]1[N:19]=[C:20]2[N:21]([CH2:24][CH2:25][CH2:26][CH:27]2[OH:28])[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (formula-10) (0.3 grams) taken in a mixture of methanol (1.5 ml) and dichloromethane (3 ml) added sodium borohydride (0.008 grams) and stirred for 1 hour at 30° C. The solvent was distilled off under reduced pressure. Methanol (1.5 ml) was added to it and heated to reflux for 30 min. the reaction mixture was cooled to 20° C. and stirred for 1 hour. Filtered the solid, washed with methanol and dried.
Reaction SMILES: C(OC(=O)CN1C2C=CC=CC=2N(CC2N(CCC(C)C)C3C=CC(C(=N)N)=CC=3N=2)C1=O)(C)(C)C.O[NH:38][C:39]([C:41]1[CH:68]=[CH:67][C:44]2[N:45]([CH2:48][C:49]3[N:53]([CH2:54][CH2:55][CH:56]([CH3:58])[CH3:57])[C:52]4[CH:59]=[CH:60][C:61]([C:63](=[NH:66])[NH:64]O)=[CH:62][C:51]=4[N:50]=3)[N:46]=[N:47][C:43]=2[CH:42]=1)=[NH:40]>>[C:63]([C:61]1[CH:60]=[CH:59][C:52]2[N:53]([CH2:54][CH2:55][CH:56]([CH3:57])[CH3:58])[C:49]([CH2:48][N:45]3[C:44]4[CH:67]=[CH:68][C:41]([C:39]([NH2:40])=[NH:38])=[CH:42][C:43]=4[N:47]=[N:46]3)=[N:50][C:51]=2[CH:62]=1)(=[NH:64])[NH2:66]
Reactant: CC(C)CCn1c(Cn2nnc3cc(C(=N)NO)ccc32)nc2cc(C(=N)NO)ccc21
Agent: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)N)ccc21
Product: CC(C)CCn1c(Cn2nnc3cc(C(=N)N)ccc32)nc2cc(C(=N)N)ccc21

Procedure:
1-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1H-benzotriazole-5-carboxamidine was prepared as described for {3-[5-carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester using N-hydroxy-1-[5-(N-hydroxycarbamimidoyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1H-benzotriazole-5-carboxamidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH:14]([NH2:16])[CH3:15]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:16][CH:14]([CH3:15])[CH:13]([O:17][CH3:18])[O:12][CH3:11])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(C)N
Reactant: S=C=Nc1cccc(Br)c1
Solvent: CCO
Product: COC(OC)C(C)NC(=S)Nc1cccc(Br)c1
Yield: 100.2 %

Procedure:
Step 1) A mixture of commercially available 3-bromophenylisothiocyanate (10.06 g, 47.0 mmol) and 2-aminopropionaldehyde dimethylacetal (5.96 mL, 47.0 mmol) in EtOH (50 mL) was refluxed for 1 h. Evaporated to dryness to give 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea as an off-white solid (15.69 g, 100%). Step 2) A mixture of the above prepared 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea (15.69 g, 47 mmol) in H2O (85 mL) and 37% HCl (8.5 mL) was refluxed for 4.5 h. Removed from oil bath, added ice and ice water (total volume: 250 mL), the precipitate was filtered off, washed several times with ice water and dried in vacuum at 60° C. to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol as a light orange solid (8.71 g, 69%). Step 3) To a suspension of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol (6.00 g, 22 mmol) in acetic acid (20 mL) and water (5 mL) was added dropwise 35% H2O2 (13.4 mL, 156 mmol) within 15 min keeping the internal temperature below 60° C. Stirred at 23° C. for 30 min, poured onto ice, destroyed excess H2O2 by addition of sat. Na2SO3-sol., adjusted pH with 32% NaOH-sol. until pH 9 is reached, extracted with EtOAc (3×100 mL), the combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a red oil, which was purified by silica gel column chromatography with EtOAc to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole as a brown oil (3.80 g, 72%). Step 4) A mixture of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole (0.313 g, 1.31 mmol), bis(pinacolato)diboron (0.364 g, 1.438 mmol), potassium acetate (0.389 g, 3.96 mmol) and PdCl2(PPh3)2 (0.023 g, 3 mol %) in DMF at 100° C. for 2 h; then addition of Pd(OAc)2 (0.007 g, 3 mol %) and dppf (0.018 g, 3 mol %) and stirred at 100° C. overnight. This solution obtained was used directly.] according to the general procedure VI. Obtained as an off-white solid (0.140 g, 32%). MS (ISP) 394.0 [(M+H)+]; mp 126-132° C.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.CO.[O:21]=[O+][O-]>ClCCl>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:21])[C:17]=2[N:16]=1
Reactant: O=[O+][O-]
Reactant: Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(=O)CCC2

Procedure:
Intermediate 200A2 in dichloromethane (100 mL)/methanol (200 mL) was cooled to −78° C. Ozone was passed through the mixture for 1-2 h until the mixture had a light blue color. The reaction mixture was purged with nitrogen followed by the addition of dimethyl sulfide (10 mL). The mixture was stirred for 30 m and evaporated. The residue was partitioned between ether and 1M HCl. The organic layer was extracted with 1N HCl (2×) and the acidic, aqueous layers were pooled, washed with ether (3×), cooled with crushed ice, and carefully basified with solid NaOH. The basic layer was extracted with chloroform, freed of solvent, and the residue was passed through a column of SiO2 with 80% ethyl acetate/hexane to give impure Intermediate 200A3 as a yellow solid. Further purification of this mixture was conducted by oxidation of the minor product: (˜3%) 8-oxo-5,6,7,8-tetrahydro-quinoline-2-carbaldehyde in formic acid (15 mL) at 0° C. by dropwise addition of H2O2 (2.1 mL, 30% solution). The mixture was stirred for 1.5 h, quenched with crushed ice, diluted with chloroform, and basified with 2 M NaOH to pH>8. The chloroform layer was dried, filtered and evaporated to give pure 2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A3), 15.1 g (50% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][N:14]([CH3:20])[C:15](=[N:18][CH3:19])SC)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([NH:29][NH2:30])(=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][N:14]([CH3:20])[C:15]3[N:18]([CH3:19])[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:29][N:30]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CN=C(SC)N(C)Cc1nc(-c2cccc(Cl)c2)no1
Solvent: ClCCl
Solvent: CCO
Product: CN(Cc1nc(-c2cccc(Cl)c2)no1)c1nnc(-c2ccncc2)n1C
Yield: 33.3 %

Procedure:
1-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1,2,3-trimethyl-isothiourea (55 mg, 0.177 mmol) was mixed with isonicotinic hydrazide (29.1 mg, 0.212 mmol) in ethanol (1 mL) at 85° C. o.n. The reaction mixture was diluted with DCM and washed with water. The product was purified by column chromatography with 5˜7% MeOH in EA and triturated with Et2O to give the title compound (22.5 mg, 40%). 1H-NMR: 8.80 (d, 2H), 8.10 (s, 1H), 8.00 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.47(t, 1H), 4.80 (s, 2H), 3.74 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]([CH2:17][CH3:18])[C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=1.[C-:21]#[N:22].[Na+].O>CN(C=O)C>[CH2:17]([N:7]1[C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[C:3]([CH2:2][C:21]#[N:22])[CH:20]=[CH:19][C:6]1=2)[CH3:18]
Reactant: [C-]#N
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CC#N)ccc21
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.11 g) in DMF(15 ml) was added sodium cyanide(0.59 g) at room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound(0.84 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)n3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 95 mg (0.34 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 16 mg (0.41 mmol) of 60% sodium hydride, 77 mg (0.41 mmol) of 2-bromomethyl-6-methyl-pyridine and 1 mL of N,N-dimethylformamide. Yield: 14 mg of a white solid: LC-MSD, m/z for C24H21N3O2 [M+H]+=384.1; HPLC retention time: 1.9 min.
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:5]=[C:6]([CH3:13])[C:7]([CH:11]=O)=[N:8][C:9]=1[CH3:10].[S:16]1C[C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.Cl>C(O)C.O>[CH:3]([C:4]1[CH:5]=[C:6]([CH3:13])[C:7](=[C:11]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])[NH:8][C:9]=1[CH3:10])=[O:14]
Reactant: COC(OC)c1cc(C)c(C=O)nc1C
Reactant: O=C1CSC(=O)N1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CC1=CC(C=O)=C(C)NC1=C1SC(=O)NC1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.7 %

Procedure:
To a mixture of 5-dimethoxymetyl-3,6-dimethyl-2-pyridinecarboxaldehyde (53 mg, 0.25 mmol) and 2,4-thiazolidindione (44 mg, 0.38 mmol) in ethanol (5 mL) was added piperidine (0.038 mL, 0.38 mmol), and the mixture was heated to reflux for 16 h. Hydrochloric acid (1 mol/L; 0.4 mL) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added tetrahydrofuran (4 mL) and hydrochloric acid (1 mol/L; 0.5 mL), and the mixture was stirred at room temperature for 7 h. Water was added, and the precipitated products were collected by filtration to afford 5-formyl-3,6-dimethylpyridin-2-ylidene-2,4-thiazolidinedione (43 mg, 66%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[CH3:7][N:8]([O:17][CH3:18])[C:9]([C:11](N(C)OC)=[O:12])=[O:10]>Cl>[CH3:7][N:8]([O:17][CH3:18])[C:9](=[O:10])[C:11](=[O:12])[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: CON(C)C(=O)C(=O)N(C)OC
Agent: Cl
Product: CON(C)C(=O)C(=O)CC1CCC1
Temperature: 0 °C
Yield: 80.3 %

Procedure:
The finely divided Mg was treated with 22.5 mL (0.20 mol) of bromomethylcyclobutane maintaining the internal temperature at <5° C. The resulting mixture was stirred cold for I h, then was treated with 26.40 g (0.15 mol) of N,N′-dimethyl-N,N′-dimethoxy oxamide (from Step A) in portions as a solid. The resulting mixture was stirred at 0° C. for 16 h. The reaction was poured onto a mixture of 100 mL conc. HCl and 500 g of ice under N2 atmosphere. The quenched mixture was extracted with 1.5 L of EtOAc. The extract was washed with 500 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 500 g of silica gel using 3:1 v/v hexanes/EtOAc as the eluant afforded 22.3 g (80%) of the title compound: 1H NMR (500 MHz) δ 1.66-1.76 (m, 2H), 1.82-1.98 (m, 2H), 2.12-2.22 (m, 2H), 2.74-2.84 (3H), 3.20 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mg].C(=O)([O:17][CH2:18][CH3:19])OCC.Cl>C(OCC)C>[CH2:2]([C:18]([CH2:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Three moles of 1-bromodecane was slowly added to 3 moles of magnesium turnings in 0.6 liters of anhydrous ethyl ether (nitrogen atmosphere). One mole of diethyl carbonate in 0.151 anhydrous ethyl ether was slowly added to the mixture. After stirring for one hour at 30° C., the mixture was slowly poured into 1.8 liters of a cold 10% HCl solution. The organic layer was dried with magnesium sulfate and the ethyl ether evaporated off to give tri-n-decylcarbinol.
Reaction SMILES: COC1C=C(C=CC=1OC)[CH2:6][N:7]([C@H:18]([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[H-].[Na+].C(N(CC)CC)C.C(Cl)(Cl)=[O:46]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH2:19][C@H:18]([N:7]2[CH2:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:10][C:6]2=[O:46])[CH3:30])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)CC(O)c2cccc(Cl)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@@H](C)N2C[C@@H](c3cccc(Cl)c3)OC2=O)cc1OC
Reaction time: 1 h

Procedure:
A solution of 0.8 g. of (R)-N-(3,4-dimethoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine in 10 mL of toluene is added to a slurry of 64 mg. of sodium hydride (60% oil slurry) in 5 mL of toluene at room temperature. The reaction mixture is stirred for one hour, 0.11 mL of triethylamine is added, and the reaction mixture is stirred for an additional 30 minutes. A 1.93M solution of phosgene (0.9 mL) is added and the reaction mixture is stirred for one hour and quenched with 10% hydrochloric acid. Additional toluene is added and the mixture is sequentially washed with dilute hydrochloric acid, 3N sodium hydroxide, and brine, after which it is dried over magnesium sulfate and concentrated to yield (R,R)-3-[1-(3,4-dimethoxyphenyl)prop-2-yl]-5-(3-chlorophenyl)oxazolidin-2-one which is further purified by recrystallization from 1:7 ethanol:heptane to yield white crystals. Gas chromatography indicates the chemical purity is 99.9% and HPLC indicates the optical purity is 99.6%. 1H NMR (250 MHz, CDCl3) d 1.26 (d, 3H, J=6.7 Hz), 2.65-2.85 (m, 2H), 3.25 (m, 1H), 3.8-3.9 (m, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 4.34 (m, 1H), 5.35 (m, 1H), 6.6-7.4 (m, 7H).
Reaction SMILES: P(=O)(O)(O)O.[I-:6].[F:7][C:8]([F:15])([F:14])[CH:9]([CH3:13])[CH2:10][CH2:11]O>>[F:7][C:8]([F:15])([F:14])[CH:9]([CH3:13])[CH2:10][CH2:11][I:6]
Reactant: [I-]
Reactant: CC(CCO)C(F)(F)F
Agent: O=P(O)(O)O
Product: CC(CCI)C(F)(F)F
Temperature: 0 °C

Procedure:
To a mixture of 19 g phosphoric acid (98%) and 19 g pottasium iodide are added at 40° under stirring 4.75 g (33.4 mMol) of 4,4,4-trifluoro-3-methyl-butan-1-ol over a period of 10 minutes. The mixture is then heated at 120° for 16 hours, a cooling poured into ice-water and extracted with diethylether. The etheric extracts are washed with 10% sodium thiosulfate and brine acid dried over sodium sulphate. After filtration, the solvent is removed through a 15 cm Vigreux-column at atmospheric pressure, followed by fractionation giving 4,4,4-trifluoro-3-methyl-1-iodo-butane, b.p. 76-77° at 140 mbar.