Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:12]([C@H:16]1[C:43](=[O:44])[N:42]2[CH2:45][C@@H:39]([CH2:40][C@H:41]2[C:46]([O:48][CH3:49])=[O:47])[O:38][C:28]2=[N:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]([OH:37])=[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:50][CH2:51][CH2:52][C@H:20]2[O:19][C:18](=[O:53])[NH:17]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C@H:16]1[C:43](=[O:44])[N:42]2[CH2:45][C@@H:39]([CH2:40][C@H:41]2[C:46]([O:48][CH3:49])=[O:47])[O:38][C:28]2=[N:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]([O:37][CH2:3][CH2:4][CH2:5][N:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:50][CH2:51][CH2:52][C@H:20]2[O:19][C:18](=[O:53])[NH:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reactant: ClCCCN1CCCCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN1CCCCC1)O2

Procedure:
The title compound was prepared using the same method as described in Example 42 using 1-(3-chloropropyl)piperidine hydrochloride as the alkylating agent with the product of Step 1. LRMS (ES+) m/z 707.5 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.CCOC(C)=O>O>[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:16]2[CH2:17][O:18]2)=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCCF)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: FCCOc1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 48 %

Procedure:
A solution of NaOH (0.35 g) in 10 mL of water was added to a mixture of 4-(2-f luoroethoxy) phenol (1.10 g, 7.1 mmol) and epichlorohydrin (0.80 mL, 10.2 mmol). The mixture was heated at 100° C. for 3 h. After cooling, the mixture is taken up with AcOEt (50 mL). The organic phase was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 4:1, as eluent) to afford pure compound in 48% yield. 1H NMR (CDCl3): δ 2.60-2.70 (m, 2H), 3.16 (m, 1H), 3.89-4.04 (m, 2H), 4.17-4.28 (m, 1H), 4.50-4.65 (m, 1H), 6.54 -6.60 (m, 2H), 6.84-6.87 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C>>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[CH:24][C:23]([O:25][CH3:26])=[CH:22][CH:21]=2)[N:15]=1
Reactant: COc1ccc(C(N)=O)c(N)c1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Product: COc1ccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 115 °C
Yield: 16.8 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (2.3 g, 10.8 mmol) and 2-amino-4-methoxybenzamide (1.5 g, 9.0 mmol) were combined with trimethylsilyl polyphosphate (15 mL) and the mixture was heated at 115° C. for 18 h with vigorous stirring. To mixture was allowed to cool to rt, and then was partitioned between were water (15 mL) and EtOAc (15 mL). The organic layer was separated and the aqueous layer (pH˜1) was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:10 to 1:1 EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4(3H)-one (487 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]4[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=4[CH:37]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1Cl
Temperature: 120 °C
Yield: 29.9 %

Procedure:
A microwave vessel was charged with 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50.00 mg, 0.1508 mmol), 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (39 mg, 0.16 mmol), 10-camphorsulfonic acid (6.0 mg, 0.026 mmol) and isopropyl alcohol (2 mL) and heated to at 120° C. for 70 minutes in a microwave reactor (sealed vessel). The reaction was diluted with water (10 mL) and saturated aqueous solution of NaHCO3 before extracting into DCM. The organic layer was dried by passing through a filter funnel loaded with MgSO4; the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 30% EtOAc/Hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (23.9 mg, 30%) as a white foam that had the following properties: m.p.=136-157° C., bubbled; LC/MS (ESI+): 529 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.12 (s, 1H), 8.03 (s, 1H), 7.62 (d, J=8.0, 1H), 7.52 (d, J=8.0, 1H), 7.31 (dd, J=8.0, 7.8, 1H), 7.27 (m, 1H), 7.220 (d, J=8.6, 1H), 7.09 (d, J=8.6, 1H), 6.98 (s, 1H), 6.10, (s, 1H), 3.7-4.2 (m, 2H), 3.55-3.47 (m, 2H), 3.30 (s, 3H), 2.95 (d, J=4.9, 3H), 2.9-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.8-2.3 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.CN(C)C=O.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([O:16][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 674.1 %

Procedure:
To an ice cooled stirred solution of methyl 5-chloro-2-(3-hydroxyazetidin-1-yl)nicotinate (D62) (66 g, 0.27 mol) and triethylamine (56.86 ml, 0.40 mol) in dimethylformamide (500 ml) methanesulfonylchloride (23.15 ml, 0.29 mol) was added dropwise maintaining the temperature at 0° C. The reaction mixture was stirred at 0° C. for 3.5 h then methanesulfonyl chloride (6.3 ml, 0.037 mol) and triethylamine (18.9 ml, 0.135 mol) were added and the reaction mixture was stirred for 3 h at 0° C. After this time the formed solid was filtered off. Water (700 ml) was added to the filtrate. The formed solid was filtered off, washed with water (400 ml) and dried under vacuo to afford the title compound (D63) (80 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.[H-].[Na+].[F:13][CH:14]([F:21])[CH2:15]OS(C)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH2:15][CH:14]([F:21])[F:13])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: CS(=O)(=O)OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(Br)ccc(Cl)c1OCC(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A solution of 3-bromo-6-chloro-2-fluorophenol (15.4 g, 0.068 mol) in DMF (25 mL) was slowly added to a suspension of sodium hydride (60% dispersion in mineral oil) (4.0 g, 0.10 mol) in DMF (100 mL) and the mixture was stirred 1 hour. A solution of methanesulfonic acid 2,2 difluoroethyl ester (17.5 g, 0.109 mol) in DMF (10 mL) was slowly added. The resulting solution was heated to 70° C. for 18 hours. The solution was diluted with water (200 mL) and extracted with ethyl ether. The combined organic phases were dried (sodium sulfate) and concentrated. The residual oil was purified by chromatography (in hexanes) to give 1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene (9.0 g, 0.031 mol): 1H NMR (CDCl3): δ 7.3 (m, 1H), 7.10 (dd, 1H), 6.15 (dt, 1H), 4.35 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][C:32]([NH:35][S:36]([C:39]1[S:40][C:41]([Cl:45])=[C:42]([NH2:44])[CH:43]=1)(=[O:38])=[O:37])([CH3:34])[CH3:33]>>[Cl:45][C:41]1[S:40][C:39]([S:36](=[O:38])(=[O:37])[NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][OH:30])=[CH:43][C:42]=1[NH:44][C:27]([C:26]1[CH:25]=[N:24][N:17]2[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:15][C:16]=12)=[O:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cc(S(=O)(=O)NC(C)(C)CO)sc4Cl)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 684.3 [(M−H)−]; mp 234° C.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=O)[CH2:10][C:4]2=[N:3][N:2]=1.B.CSC.CO>O1CCCC1>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: O=C1Cc2nncn2-c2ccccc2N1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCc1nncn1-2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g of 5,6-dihydro-4H-[1,2,4]-triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled to room temperature and ml of methanol added dropwise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted with dichloromethane. The extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12]>CO.O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C=CC(=O)c1ccccc1N
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)CCC(=O)c1ccccc1N
Yield: 76.2 %

Procedure:
A solution of 4.87 g (23.73 mM) of methyl 4-(2-aminophenyl)-4-oxo-2-butenoate in 120 ml of methanol and 6 ml of water is hydrogenated in the presence of 974 mg of 10% Pd-C at room temperature under atmospheric pressure. After removal of the catalyst, the mixture is concentrated to give a residue, which is chromatographed on a column of silica gel (274 g), eluting with toluene-ethyl acetate (30:1-19:1 v/v) to give 3.746 g of methyl 4-(2-aminophenyl)-4-oxobutyrate as orange crystals. This is recrystallized from Et2O-n-hexane to give 3.162 g (Yield: 64.3%) melting at 50.0°-51.0° C. as yellow crystals.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]([OH:29])=O)[CH2:20][CH2:19]1)[CH3:17].[Br:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([NH2:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1>O1CCCC1.N1C=CC=CC=1>[Br:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([NH:48][C:27](=[O:29])[C:26]#[C:25][CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:23][CH2:22]4)[CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN1CCN(CC#CC(=O)Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Isobutyl chloroformate (0.847 g, 6.2 mmol) and N-methylmorpholine (1.460 g, 14.4 mmol) were added to an ice cold solution of 1.900 g (9.52 mmol) of 4-(4-ethyl-piperazin-1-yl)-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (30:70), gave 1.450 g of 4-(4-Ethyl-piperazin-1-yl)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 493.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH2:6][CH2:5][N:4]([CH2:14][CH2:13][CH2:12][Br:11])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)NCCS2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCN1CCSc2ccccc21
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (2.0 g, 1.0 eq, 13.24 mmol), 1,3-dibromopropane (14 ml, 10 eq, 132.4 mmol) and anhydrous Na2CO3 (4.21 g, 3.0 eq, 39.7 mmol) in dry DMF (130 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water and brine. The organic layer was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as yellow oil (2.13 g, 59% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].Br[CH2:11][C:12]([CH2:14][C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16])=O.Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:11]=[C:12]([CH2:14][C:15]([NH:17][CH:18]2[C:28](=[O:29])[N:20]3[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]23)=[O:16])[N:4]=1
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 51.1 %

Procedure:
Thiourea (663 mg), sodium bicarbonate (732 mg) and water (20 ml) were added to a stirred solution of 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid (2.11 g) in tetrahydrofuran (20 ml) under ice-cooling and stirred at the same temperature for an hour. After the resultant solution was adjusted to pH 4.0 with dilute hydrochloric acid, the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (1.01 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].C(N(CC)CC)C>O1CCCC1>[C:2](=[O:3])([O:15][CH2:14][CH:12]1[O:13][CH2:11]1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC1CO1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCC1CO1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A three-necked round bottom flask, equipped with a reflux condenser, an addition funnel, and a nitrogen gas inlet is charged with 25.00 g (0.160 mole) of phenyl chloroformate and 70 g of THF. The reactor was placed in a 0° C. bath and purged with nitrogen. After 30 minutes, a solution of 13.00 g (0.175 mole) glycidol, 19.50 g (0.193 mole) triethylamine, and 75 g of anhydrous tetrahydrofuran (THF) was added drop wise over the course of one hour, after which the reaction was allowed to warm to room temperature and allowed to stir overnight under a nitrogen atmosphere. The contents of the reactor were discharged, filtered, and evaporated to dryness to afford 29.51 g of crude product, which was purified by flash chromatography using silica gel and eluted with a 1:1 solution of iso-propyl acetate and hexane. See FIG. 10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[C:18](OC)(OC)(OC)[CH:19]([CH3:21])[CH3:20]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:18]1[CH:19]([CH3:21])[CH3:20]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: COC(OC)(OC)C(C)C
Solvent: CC(=O)O
Product: Cc1ccsc1C1Cc2ccccc2N=C(C(C)C)N1C
Yield: 26.5 %

Procedure:
A solution of 5.86 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 19.56 g of trimethyl orthoisobutyrate was treated rapidly with 7.94 ml of glacial acetic acid. The solution was refluxed for 8 hours under nitrogen and concentrated on a rotary evaporator at 40° C. The residual oil was acidified with 10% hydrochloric acid solution and extracted with ether (3×100 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane (3×100 ml). The organic phases was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Purification was accomplished by HPLC (Water's Associates Prep LC/System 500A, silica gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of the appropriate fractions yielded 1.88 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl-2-thienyl)-3H-1,3-benzodiaze pine as an oil. The oil was treated with ethereal hydrogen chloride and the resulting precipitate was triturated with ether to yield 1.80 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl-2-thienyl)-3H-1,3-benzodiazepine hydrochloride, mp 240.5°-241.0° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylate (137.7 mg, 0.28 mmol, 1.00 equiv) in methanol/THF (1:1) (10 mL), and sodium hydroxide (56 mg, 1.40 mmol, 5.00 equiv) in water (3 mL) were placed in a 50-mL round bottom flask and stirred for 2 h at 40° C. in an oil bath. The mixture was concentrated by vacuum and filtered. The resulting solution was concentrated under vacuum, and the resulting solid washed with DCM/MeOH (5:1) resulting in 45 mg (33%) of 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([Cl:15])[CH:6]=1)=[O:4].[NH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C.C(N(CC)CC)C>C(O)C>[ClH:15].[ClH:15].[CH3:1][N:2]([CH3:16])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)c1cc(NCCCN)nc2ccccc12
Product: Cl
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A solution of 2-chloroquinoline-4-carboxylic acid dimethylamide (512 mg, 2.18 mmol), tert-butyl N-(3-aminopropyl)carbamate (571 μl, 3.27 mmol), and triethylamine (608 μl, 4.36 mmol) in absolute ethanol (35 ml) was heated at reflux for 7 days. The reaction was then allowed to cool to ambient temperature and was evaporated under reduced pressure to give a yellow oil. The residue was purified by column chromatography (ethyl acetate), dissolved in methylene chloride (10 mL), and treated with 4 N hydrogen chloride in dioxane (3 mL). The reaction was maintained at ambient temperature for 24 hours. Evaporation under reduced pressure gave 2-(3-aminopropylamino)quinoline-4-carboxylic acid dimethylamide dihydrochloride (218 mg, 30%) as a pale yellow solid. [M+H]+ 273.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][N:10]=1)=[O:5])C.[CH2:20]([NH2:22])[CH3:21]>CO.O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[O:7][C:6]([C:4](=[O:5])[NH:22][CH2:20][CH3:21])=[N:10][N:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reactant: CCN
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reaction time: 1.5 h

Procedure:
To a solution of 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (prepared as described in JOC (1995), 60(10), 3112-20) (0.150 g) in methanol (5 ml) was added a solution of 2.0M ethylamine in tetrahydrofuran (3 ml). The solution was left standing at 20° C. for 1.5 h. The solvent was removed by evaporation using a stream of nitrogen to give the title compound as a yellow gum (0.139 g).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)([O-:5])=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C(OCC)(=O)C>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:24](/[CH:25]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:20][CH:19]=2)[CH:23]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(/C=C/c2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
A suspension of 677 mg of sodium hydride (55% dispersion in oil) in 10 ml of N,N-dimethylformamide are cooled to 0° C. Thereupon, 5.61 g (20.5 mmol) of diethyl (4-nitrobenzyl)phosphonate are added portionwise. The reaction mixture is left to warm to RT and stirred for 1.5 hours. Thereafter, the mixture is cooled to −101° C. and a solution of 1.5 g (12.1 mmol) of 3-fluorobenzaldehyde in 5 ml N,N-dimethylformamide is added dropwise. Stirring is continued for 30 min at 0° C., then at RT. For the working-up, ice and ethyl acetate is added to the reaction mixture. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure to yield the crude crystalline product, which after recrystallisation from a mixture of ether and heptane gives 2.41 g (82% of theory) of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=243 (M)+.