Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:35].[ClH:37].[Cl:36][C:17]1[C:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3Cl)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 8-[3-[4-(tert-butoxycarbonyl)piperazine-1-carbonyl]-2,6-dichlorobenzyloxy]-2-methylquinoline (260 mg) and 4N solution of hydrogen chloride in ethyl acetate (2 ml) was stirred for 40 minutes at ambient temperature. The mixture was concentrated in vacuo, and the residue was crystallized from acetonitrile to give 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (227 mg) as pale yellow crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:49])[NH:6][C:7]2[CH:47]=[CH:46][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:29]6[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:48])[CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[NH:31]1[CH2:30][CH:29]([N:28]([CH2:27][C:24]2[CH:25]=[N:26][C:21]([C:19]3[S:20][C:13]4[C:14](=[N:15][CH:16]=[CH:17][C:12]=4[O:11][C:10]4[CH:46]=[CH:47][C:7]([NH:6][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:49])=[CH:8][C:9]=4[F:48])[CH:18]=3)=[CH:22][CH:23]=2)[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:32]1
Reactant: CCOC(=O)CN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C1CNC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 431 (93 mg, 0.135 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane solution (0.17 mL, 0.675 mmol) and stirred at RT for 6 h. The mixture was then concentrated to afford the title compound 432 (presumably the hydrochloride salt) as beige solid which was used in the next step with no additional purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.13 (s, 1H), 8.98-8.86 (m, 1H), 8.78-8.66 (m, 1H), 8.69 (d, J=6.0 Hz, 1H), 8.63 (d, J=1.2 Hz, 1H), 8.40 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.77 (dd, J=13.6, 2.4 Hz, 1H), 7.44 (t, J=9.0 Hz, 1H), 7.25-7.21 (m, 1H), 6.92 (d, J=5.2 Hz, 1H), 6.77 (brs, 1H), 4.08 (q, J=7.2 Hz, 2H), 4.15-3.80 (m, 7H), 3.16 (s, 2H), 2.58-2.51 (m, 1H), 1.19 (t, J=7.2 Hz, 3H), 0.68-0.62 (m, 2H), 0.45-0.39 (m, 2H). MS (m/z): 591.58 (M+H).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[NH:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22]2[N:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCNCC2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
1-chloroethyl chloroformate (2.9 g, 20 mmol) was added dropwise to a stirring mixture of 6-(1-benzyl-piperidin-4-yl)-pyridazin-3-carbonitrile (D2) (1.5 g, 5.1 mmol) and diisopropylethylamine (2.6 g, 20 mmol) in dichloromethane (50 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then the solvent evaporated in vacuo. Methanol (50 ml) was added to the residue and the mixture was refluxed for 2 h. The solvent was evaporated in vacuo and the residue purified by column chromatography (silica gel; 5-12% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and the solvent evaporated in vacuo to yield D3 (0.9 g, 90%) as a solid. C10H13N5 requires 203. Found 204 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[C:12]([O:16][C:17](=O)[O-:18])([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:5]2
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: O=C1NCc2cc(Br)ccc21
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.5 mg of 5-bromo-1-oxo-isoindoline was dissolved in 20 ml of tetrahydrofuran, cooled down to 0° C. Then, 85 mg of N,N-dimethylaminopyridine and 3.0 ml of tert-butylcarbonate were added, and the mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 300 mg of the above compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O.[BH4-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:13])=[CH:4][C:3]=1[Cl:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1c(N)ccc2c1C(O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N)c(Cl)cc2c1C(O)CC2
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A solution of 6-amino-7-cyanoindan-1-ol (700 mg, 4 mmol) in tetrahydrofuran (50 ml) is treated with N-chlorosuccinimide (530 mg, 4 mmol) in portions over 20 minutes, stirred for 30 minutes, treated with sodiumborohydride (270 mg), and stirred for one hour. The mixture is quenched with water (30 ml), evaporated to remove tetrahydrofuran, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered, and evaporated to give 6-amino-5-chloro-7-cyanoindan-1-ol (400 mg) which is directly used in the next step; LC/MS: 209/211 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]([C:22]1[CH:34]=[CH:33][C:25]2[N:26]([CH2:30][O:31][CH3:32])[C:27](=[O:29])[S:28][C:24]=2[CH:23]=1)([C:11]1[N:15](C2CCCCO2)[N:14]=[CH:13][CH:12]=1)[CH3:10].C(Cl)Cl>>[CH3:32][O:31][CH2:30][N:26]1[C:25]2[CH:33]=[CH:34][C:22]([C:9]([C:11]3[NH:15][N:14]=[CH:13][CH:12]=3)=[CH2:10])=[CH:23][C:24]=2[S:28][C:27]1=[O:29]
Reactant: COCn1c(=O)sc2cc(C(C)(O)c3ccnn3C3CCCCO3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccc2c(c1)sc(=O)n2COC)c1ccn[nH]1
Yield: 92 %

Procedure:
Add trifluoroacetic acid (20 Eq (molar), 2.26 moles, 170 mL) to a solution of 6-[1-hydroxy-1-(1-tetrahydropyran-2-yl-1H-pyrazol-5-yl)ethyl]-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one (44 g, 113 mmoles) in DCM (0.2 M, 8.81 moles, 565 mL) and stirr at room temperature over night (˜16 hr.). Concentrate the resulting dark purple reaction mixture, dissolve it in EtOAc (2 L) and neutralize the solution by slowly adding saturated aqueous sodium bicarbonate. Transfer to a separatory funnel and extract into EtOAc, wash with water (300 mL) and then brine (300 mL). Dry over Na2SO4, filter, and concentrate. Purify the material by HPLC, eluting with EtOAc/Hexanes (1:1) to give 3-(methoxymethyl)-6-[1-(1H-pyrazol-5-yl)ethenyl]-3H-1,3-benzothiazol-2-one (30 g, 104 mmoles, 92% yield) as a thick yellow oil. LCMS (Low) desired product peak at rt=1.82 min., M+1=288.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].C1CCC(N=C=NC2CCCCC2)CC1>CC#N>[C:31]1(=[O:36])[N:30]([N:24]([C:22](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:25][C:26]([OH:28])=[O:27])[C:34](=[O:35])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)O)N1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 67.6 %

Procedure:
To a solution of acid 58 (887 mg, 2.20 mmol) in dry MeCN (11 mL) at 0° C. was added N-hydroxysuccinimide (278 mg, 2.42 mmol) and DCC (499 mg, 2.42 mmol). After stirring for 4.5 h at 0° C., the reaction mixture was filtered, solids were washed with several small portions of MeCN and the combined filtrates were concentrated to dryness. The crude product was purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 60-75% EtOAc in CH2Cl2 as eluent. Evaporation of pure fractions yielded compound 59 (744 mg, 68%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.35-1.53 (m, 3H), 1.44 (s, 18H), 1.61-1.71 (m, 2H), 1.83-1.92 (m, 1H), 2.85 (s, 4H), 3.07-3.13 (m, 2H), 4.10-4.15 (m, 1H), 4.40 (d, J=5.7 Hz, 2H), 4.62 (bs, 1H), 5.16 (bs, 1H), 6.86 (bs, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=4[N:19]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2>C(#N)C.CN(C)C=O>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][N:28]([C:17]1[C:18]3[N:19]=[C:10]([C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=1)[CH2:27][CH2:26]2
Reactant: O=c1[nH]cnc2ccc(-c3cnc4[nH]ccc4c3)nc12
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2c(cc1OC)CN(c1ncnc3ccc(-c4cnc5[nH]ccc5c4)nc13)CC2
Temperature: 60 °C
Yield: 51 %

Procedure:
0.20 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and 0.22 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are suspended in 10 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.65 g of (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate, 255 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are subsequently added, and the mixture is heated at 60° C. under nitrogen until the reaction has proceeded to completion (HPLC check, about 5 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.17 g of 4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine (“A7”) as white solid (yield 50%, content 97%); MS-FAB (M+H+)=439; Rf (polar method): 1.68 min;
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.CN(C)C=O.C(Cl)Cl.CO>O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNc1ccc2[nH]ncc2c1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC(CNCCNc1ccc2[nH]ncc2c1)COc1ccccc1
Reaction time: 24 h

Procedure:
3.0 g. Phenyl glycidyl ether and 7.0 g. 5-(2-aminoethylamino)-indazole are dissolved in 10 ml. dimethylformamide by briefly heating to 70° C. and then left to stand for 24 hours at ambient temperature. The reaction mixture is shaken with 400 ml. methylene chloride-methanol (8:2 v/v) and 200 ml. water. The organic phase is evaporated and the residue obtained is purified by column chromatography on silica gel using, as elution agent, methylene chloride-methanol (9:1 v/v) and methylene chloride-ammonia-saturated methanol (9:1 v/v). The residue of the pure fractions is boiled under reflux for 1 hour with 50 ml. ethyl acetate and, after cooling, filtered off with suction and recrystallized from isopropyl alcohol, with the use of active charcoal. There are obtained 1.7 g. (26% of theory) of the desired product in the form of almost colorless crystals, which sinter at 137° C. and melt at 141°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To 2-chloro-5-nitroaniline (2 g, 11.59 mmol) in pyridine (5 mL) at room temperature was added 4-methylbenzoyl chloride (1.6 mL, 12.17 mmol), followed by pyridine (5 mL). The mixture was then stirred at room temperature for 16 h. Ethyl acetate was then added to the solution to give a precipitate, which was filtered off and washed twice with ethyl acetate, and then hexanes. The resulting solid was then washed with aqueous sodium bicarbonate, 1M aqueous sodium hydroxide, water and hexanes to afford (1.4 g, 42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](\[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])/[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccccc1Cl
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccccc1Cl
Temperature: 85 °C

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234.72 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-chlorobenzene (277.82 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.34 (m, 2H), 7.24 (d, 1H), 7.12 (d, 2H), 6.95 (m, 1H), 6.70 (m, 2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.25 (m, 2H), 3.10 (m, 2H), 3.0 (m, 2H), 2.80 (s, 3H), 2.34 (s, 3H)
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[H][H].CO.C(Cl)Cl>C(O)C.[Pd]>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(S(N)(=O)=O)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCCc1cc(S(N)(=O)=O)ccc1O
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A Parr hydrogenation flask was charged with a solution of 3.04 g (14.30 mmol) of the product of Step A dissolved in 25 mL of ethanol and 0.300 g of a 10% palladium on carbon catalyst was added. The flask was mounted in the hydrogenation apparatus, freed of air, pressurized with hydrogen (40 psig) and shaken for 15 minutes. At the end of this period TLC analysis (3% MeOH--CH2Cl2, 2 elutions) indicated that the reaction was complete and the reaction mixture was filtered and evaporated. The product was dried in vacuo to afford 3.06 g (99%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(OP(Cl)([Cl:30])=O)=CC=1.[OH-].[NH4+]>>[Cl:30][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc(C(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat 55 g. of the crude 5-(diphenylmethyl)-2-pyridone and 110 ml. of phenylphosphoric dichloride at 200°-210° with stirring for 6 hours. Pour the cooled reaction mixture onto ice, basify with ammonium hydroxide, extract with ethyl ether, dry the ether extracts, and concentrate to a residue. Distill the residue at 160°-175°/0.15 mm. and crystallize the distillate from hexane to obtain 2-chloro-5-(diphenylmethyl)-pyridine, m.p. 69.5°-71°.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:18])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[N:19]([O-])=[O:20].[Na+]>C(O)(=O)C.O>[OH:20][N:19]=[C:4]([C:3]([CH2:2][Cl:1])=[O:18])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(CCl)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)C(=NO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
In 100 ml of acetic acid is dissolved 50 g (0.184 mol, uncorrected for purity) of the crude p-nitrobenzyl γ-chloroacetoacetate obtained in 1), and the solution is cooled to 5° C. or lower, and a solution of 12.7 g (0.184 mol) of sodium nitrite in 50 ml of water is added dropwise thereto at 5° C. or lower over a period of an hour. After completion of the addition, the mixture is stirred for 30 minutes and poured into 600 ml of ice water and extracted with 300-ml and 200-ml portions of ethyl acetate. The organic layers are combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness to give 54.0 g of p-nitrobenzyl α-hydroxyimino-γ-chloroacetoacetate as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:38][C:39]([O:41][CH3:42])=[O:40])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2nccc(-c3ccncc3)c2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of 4-(4-pyridinyl)-6-quinolinecarbaldehyde (2.29 g, 9.78 mmol), methyl (triphenylphosphoranylidene)acetate (3.30 g, 9.78 mmol) in MeOH (75 mL) was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the resulting residue was purified by silica gel chromatography (1% MeOH in EtOAc) to give the title compound (2.71 g, 95%) as a white solid. MS (ES)+ m/e 291 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]([CH2:11][C:12]([NH:14][C@H:15]1[C@H:18](S(C2C=CC=CC=2)(=O)=O)[NH:17][C:16]1=[O:28])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>[Cl-].[Cl-].[Mg+2].O1CCCC1>[O:4]([CH2:11][C:12]([NH:14][C@H:15]1[C@@H:18]([CH3:1])[NH:17][C:16]1=[O:28])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]Cl
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@H]1S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Methyl magnesium chloride (2.9 ml, of 2.9 M in tetrahydrofuran) was added to a solution of 500 mg (3R-trans)-3-phenoxyacetylamino-4-phenylsulfonyl-2-azetidinone in 11.1 ml of 0.5 M magnesium dichloride in tetrahydrofuran under nitrogen and chilled in an ice/acetone bath (-10° C.). After 2 hours, the mixture was added to saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and evaporated. Treatment of the residue with dichloromethane/ethyl ether gave 106 mg of cis-3-phenoxyacetylamino-4-methyl-2-azetidinone. The corresponding trans isomer, as well as some cis isomer, was present in the mother liquor, as shown by NMR.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]2=[O:11])=[CH:15][CH:16]=1
Reactant: Oc1ccc2ccccc2n1
Reactant: Clc1ccc(CBr)cc1
Product: O=c1ccc2ccccc2n1Cc1ccc(Cl)cc1
Yield: 79.7 %

Procedure:
According to Scheme 12: The title compound was prepared from quinolin-2-ol (1 eq, 0.69 mmol, 0.10 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 1.03 mmol, 0.21 g) according to the procedure described for Example 1, Step 2. Reaction conditions: 17 hours under reflux. The residue was purified by flash chromatography on silica gel using pure CH2Cl2 as eluent to afford 1-(4-chlorobenzyl)quinolin-2(1H)-one as a white solid (0.55 mmol, 0.15 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18].[H-].[Na+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCCNS(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (90 μL, 0.70 mmol) and 2-amino-N-propyl-benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80° C. for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the title compound as a slightly yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)[CH2:6][C:5]2=[O:19].[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:10]1([CH3:14])[O:11][CH2:12][C:7]2([CH2:6][C:5](=[O:19])[C:4]3[C:16](=[CH:17][CH:18]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])[CH:3]=3)[O:15]2)[CH2:8][O:9]1
Reactant: CC1(C)OCC2(CO1)CC(=O)c1cc(Br)ccc1O2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OCC2(CO1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 100 °C
Yield: 56.9 %

Procedure:
To a solution of 6-bromo-2′,2′-dimethylspiro[chroman-2,5′-[1,3]dioxan]-4-one (498 mg, 1.5 mmol), 3-cyanophenylboronic acid (440 mg, 3.0 mmol) and Cs2CO3 (1.460 mg, 4.5 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (75 mg). After degassed by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (12 g, eluted with ethyl acetate in hexane 0-30%) give 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile as a yellowish solid (298 mg). MS ESI +ve m/z 350 (M+H)+.