Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:13]1([C:16]2[CH:21]=[CH:20][C:19]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[O:30]COCC[Si](C)(C)C)=[O:23])=[CH:18][CH:17]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH:13]1([C:16]2[CH:17]=[CH:18][C:19]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[OH:30])=[O:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15]1
Reactant: C[Si](C)(C)CCOCOc1cnccc1C(=O)c1ccc(C2CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(C2CC2)cc1)c1ccncc1O
Temperature: 65 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
p-Toluenesulfonic acid monohydrate (3.03 g, 15.9 mmol) was added to a solution of (4-cyclopropylphenyl)-[3-(2-trimethylsilylethoxymethoxy)pyridin-4-yl]methanone (1.96 g, 5.30 mmol) in THF (49 mL) and the mixture solution was stirred at 65° C. for one hour. The reaction mixture was cooled to room temperature and a saturated sodium hydrogencarbonate aqueous solution was added thereto and the mixture was extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography [developing solution=n-hexane:ethyl acetate (2:3)] to obtain the title product (1.10 g, 87%).
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:11]1[CH:16]=[C:15]2[C:17](Br)=[C:18](Br)[S:19][C:14]2=[CH:13][CH:12]=1>C(Cl)Cl.Cl[Pd]Cl>[CH2:3]([O:2][P:1]([C:18]1[S:19][C:14]2[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=2[C:17]=1[P:1]([O:2][CH2:3][CH3:4])([O:5][CH2:6][CH3:7])=[O:8])([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: CCOP(OCC)OCC
Reactant: Brc1sc2ccccc2c1Br
Agent: Cl[Pd]Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1sc2ccccc2c1P(=O)(OCC)OCC
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A suspension of PdCl2 (0.15 g) in 2,3-dibromothianaphthene (2.4 g) was brought to the temperature of 115° C., and P(OEt)3 (3.3 g) was then dropped under stirring and in an inert atmosphere. Once dropping was completed, the red solution was brought to 160° C. After 1 h 30 min, the mixture was diluted with CH2Cl2, washed twice with water and dehydrated. The solvent was evaporated at reduced pressure to yield a residue that underwent chromatography on silica gel by flash chromatography (AcOEt), to yield 2,3-bis(diethoxyphosphoryl)-benzo[b]thiophene (1.6 g) (yield 60%).
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)=[O:20].C([O-])(O)=O.[Na+]>ClCCl>[CH3:18][S:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: CS(=O)Cl
Reactant: C1CCC2NCCCC2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)N1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A solution of decahydroquinoline (1.07 g, 7.68 mmol) in anhydrous dichloromethane (10 mL) was cooled to −15° C. The reaction mixture was treated with triethylamine (1.07 mL, 7.68 mmol) and methanesulfinyl chloride (800 mg, 8.11 mmol). After 1 hour, the reaction mixture was placed in a −40° C. freezer overnight. The reaction mixture was warmed to room temperature and treated with 5% aq. NaHCO3 (10 mL) and additional dichloromethane (10 mL) and was separated. The organic layer was washed with 3% aq. HCl (1×20 mL), 5% aq. NaHCO3 (2×20 mL), water (1×20 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as a yellow oil (1.2 g, 77%): 1H NMR (CDCl3, 600 MHz, δ) 3.41-2.70 (m, 4H), 2.52 (s, 1.3H, C1′-H), 2.51 (s, 0.4H, C1′-H), 2.49 (s, 1.3H, C1′-H), 1.75-1.26 (m, 12H); 13C NMR (CDCl3, 125 MHz, δ) 54.2, 49.2, 48.3, 47.8, 43.2, 42.6, 42.3, 41.6, 41.5, 41.4, 41.6, 41.5, 41.4, 39.0, 38.9, 38.84, 38.77, 35.6, 35.4, 34.0, 33.9, 33.1, 32.6, 32.5, 30.1, 30.0, 26.0, 25.7, 25.6; ESIMS m/z 224.2 (4, MNa+), 204.1 (5, 32S), 203.0 (13, 13C), 202.0 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: NC(N)=S.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6].[C:28]([N:32]=[C:33]=[S:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:33]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[S:34])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)(C)N=C=S
Agent: NC(N)=S
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=S)NC(C)(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Thiourea formation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with tert-butyl isothiocyanate (7.5 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 18.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=[O:22])[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][CH:31]=[CH2:32]>CN(C=O)C>[CH2:32]([O:22][C:5]1[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:31]=[CH2:30]
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(SC)nc(C(=O)OCC)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 2-methylsulfanyl-1,6-dihydro-6-oxo-5-(phenylmethoxy)-4-pyrimidinecarboxylic acid, ethyl ester (4.28 g, 13.36 mmol) in DMF (70 mL) was added Cs2CO3 (4.35 g, 13.36 mmol) followed by 3-bromoprop-1-ene (1.156 mL, 13.36 mmol). The resulting mixture was stirred at 80° C. for 1 h, cooled to room temperature and partitioned between ethyl acetate and hexane. The organic phase was washed with water followed by brine, dried (Na2SO4) and filtered. Concentration gave an oil that was purified by flash column chromatography (Biotage flash chromatography system, 0%-40% ethyl acetate/hexane, 16 CV) to give the title compound as a yellow oil (1.8144 g, 38% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41-7.37 (2H, m), 7.36-7.28 (3H, m), 6.10-5.97 (1H, m), 5.40 (2H, dq, J=17.2, 1.5 Hz), 5.29 (2H, dq, J=10.5, 1.2 Hz), 5.03 (2H, s), 4.93 (2H, dt, J=5.6, 1.4 Hz), 4.32 (2H, q, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 2.50 (2H, q, J=7.1 Hz), 1.28 (3H, t, J=7.1 Hz). LCMS (M+H) calcd for C18H21N2O4S: 361.12; found: 361.21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[CH:10]=1
Reactant: COC(=O)CCc1c[nH]cn1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(Cc2cc(-c3ccc(Cl)s3)on2)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 190 mg of 3-(1H-Imidazol-4-yl)-propionic acid methyl ester (hydrochloride salt) in DMF (5 mL) was added K2CO3 (414 mg) and 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (278 mg). The mixture was stirred for 2 h at 70° C. After removal of the solvent in vacuo the residue was taken up in ethyl acetate. The mixture was washed with water and brine. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure to give crude 3-{1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazol-4-yl}-propionic acid methyl ester (174 mg) as a brown solid which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH:20]([O:22][CH2:23][CH3:24])[CH3:21])[CH:14]=[CH:13][CH:12]=3)=[O:5])C.[OH-].[Na+].C(O)C>C(O)(=O)C>[CH2:23]([O:22][CH:20]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:18]([CH3:19])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8][C:9]=1[NH:10]2)[CH3:21])[CH3:24]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(C(C)OCC)c3c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(C)c1cccc2[nH]c3cnc(C(=O)O)c(C)c3c12
Yield: 87.5 %

Procedure:
500 mg of 5-(1-ethoxyethyl)-4-methyl-beta-carboline-3-carboxylic acid ethyl ester was refluxed with 5 ml of 1N sodium hydroxide solution and 20 ml of ethanol for 3 hours. Then it was acidified with glacial acetic acid, suctioned off and washed with water. 400 mg of 5-(1-ethoxyethyl)-4-methyl-beta-carboline-3-carboxylic acid was obtained, which after good drying over phosphorus pentoxide in a vacuum was further reacted.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[NH2:14][C@@H:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16].Cl[CH2:24][C:25](O)=[O:26]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:14]([C@@H:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])[C:25](=[O:26])[CH2:24][S:13]1
Reactant: O=C(O)CCl
Reactant: C[C@@H](N)C1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(=O)N1[C@H](C)C1CCCCC1

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1R)-1-cyclohexylethyl)-1,3-thiazolidin4-one.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[C@@H:10](Br)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:15]=[N+]=[N-].[Na+].O.C([O-])(O)=O.[Na+]>CN(C)C=O>[NH2:15][C@H:10]([CH2:11][OH:12])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(NCc1ccccc1)[C@@H](Br)CO
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 52.5 °C

Procedure:
To a reaction flask charged (2S)-N-benzyl-2-bromo-3-hydroxypropanamide (80.0 gms) and sodium azide (30.23 gms) in N,N-dimethylformamide (480 ml), stirred and raised the temperature to 50-55° C. and maintained for 4-5 hours. Stopped heating and cooled the reaction mixture to 20-25° C., charged DM water (400 ml), adjusted pH of the reaction mixture to 9-9.5 using 5% NaHCO3 solution. Extracted the reaction mixture with ethyl acetate (1×800 ml, 2×280 ml) separated the organic layer and combined all ethyl acetate layers, washed with saturated ammonium chloride solution (2×240 ml). The ethyl acetate layer was taken for hydrogenation to 2 lit autoclave. Charged ethyl acetate layer and 5% Pd-C (6.85 gms) was added and closed the autoclave. Applied 3.8 kg Hydrogen pressure maintaining temperature at 25-30° C. and maintained the reaction mixture at 25-30° C. for 1.0 hour. After completion of the reaction released Hydrogen pressure and flushed the autoclave with Nitrogen gas. Filtered the reaction mass through hyflo bed and washed hyflo bed with ethyl acetate. Concentrated filtrate under reduced pressure at 30-35° C. till two volumes of ethyl acetate remains in the reaction mixture. Removed vacuum and cooled the reaction mass to 0-5° C. and maintained for 2.0 hours. The reaction mass was filtered and washed with cold ethyl acetate (2×40 ml). Dried the product (2R)-2-amino-N-benzyl-3-hydroxypropanamide under vacuum at 25-30° C. till constant weight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][CH2:25][CH2:24][CH2:23]2.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[C:7]([C:8]([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:19])=[C:29]([F:30])[CH:28]=3)[CH2:23][CH2:24][CH2:25]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: Fc1cc2c(cc1F)NCCC2
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=C(c1cccnc1Oc1ccc(F)c(Cl)c1)N1CCCc2cc(F)c(F)cc21
Temperature: 60 °C
Yield: 9.4 %

Procedure:
To a solution of 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (32.1 mg, 0.12 mmol, 1.0 equiv; Example 77, Step 1) in dichloromethane (1 mL) was added 6,7-difluoro-1,2,3,4-tetrahydro-quinoline (24.4 mg, 0.14 mmol, 1.2 equiv; [CAS RN 953717-64-1]), tri-n-butylamine (111.2 mg, 143 μL, 0.60 mmol, 5.0 equiv; [CAS RN 102-82-9]) and 2-chloro-1-methylpyridinium iodide (36.8 mg, 0.14 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was heated by microwave irradiation to 60° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.7 mg (9%) of the title compound. MS (ISP): 419.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3)[CH3:2].CC(O)=[O:20].OO>O>[CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:20])[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3)[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1nnc2cnc3cc(Cl)c(Cl)cc3n12
Agent: OO
Solvent: O
Product: CCc1nnc2c(=O)[nH]c3cc(Cl)c(Cl)cc3n12
Temperature: 50 °C

Procedure:
The triazole (3) (1.5 g, 5.64 mmol) was added to 47 ml of HOAc, and then 14 ml 30% H2O2 added. The mixture was warmed 4 hours at 50° C., then cooled to room temperature and poured into H2O. The precipitate was filtered and dried, yielding 1.09 g of 1-ethyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (4).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([F:33])[CH:25]=1.CC(C)=O>CC(C)=O.O>[CH2:10]([O:9][CH2:8][CH2:7][CH:3]([NH:2][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Br:23])=[CH:25][C:26]=1[F:33])[C:4]([OH:6])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(CCOCc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(CCOCc1ccccc1)C(=O)O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-amino-4-benzyloxy-butyric acid hydrochloride salt (1.0 mmol) (See Intermediate 34) and sodium carbonate (3.0 mmol) in 1:1 acetone/water (0.5M) in a 0° C. ice bath, slowly add 4-bromo-2-fluoro-benzoyl chloride (1.2 mmol) diluted in acetone (prepared from 4-bromo-2-fluoro-benzoic acid (1.0 mmol) and oxalyl chloride (1.0 mmol) in dichloromethane using catalytic dimethylformamide). Stir for 30 minutes at 0° C. After this time, wash the reaction with 1N hydrochloric acid while extracting with ethyl acetate. Concentrate the organics in vacuo. Purify on an Isco CombiFlash® chromatography system eluting with 1% acetic acid in ethyl acetate and hexane. MS (m/e) (79Br/81Br): 410.3/412.3 (M+1)
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:40])[C:11]([NH:32]C(=O)OC(C)(C)C)=[CH:12][N:13]([CH2:26][CH:27](OC)OC)[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:24].[NH2:32][C:11]1[C:10](=[O:40])[C:9]([OH:8])=[C:14]2[C:15](=[O:25])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH:27]=[CH:26][N:13]2[CH:12]=1
Reactant: COC(Cn1cc(NC(=O)OC(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 185.7 %

Procedure:
tert-Butyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]carbamate (40 mg) was dissolved in acetic acid (0.4 ml) and conc. hydrochloric acid (0.4 ml) was added. The mixture was stirred at 90° C. for 5 hr. The reaction mixture was concentrated, toluene was added to the residue and the mixture was concentrated, which operations were performed twice. Methanol was further added, and the mixture was concentrated, which operations were performed twice. Crystallization from ethyl acetate-methanol-diisopropyl ether gave 7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (23 mg).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[C:20]([Cl:21])=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][C:12]=1[Cl:22]>C1COCC1>[Br:10][C:11]1[C:20]([Cl:21])=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[Cl:22]
Reactant: COC(=O)c1cc(Cl)c(Br)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
DIBAL-H (1M in toluene, 66 mL, and 66.0 mmol) was added dropwise to a stirred solution of methyl 4-bromo-3,5-dichlorobenzoate (7.5 g, 26.0 mmol) in THF (50 mL) at −78° C. The reaction mixture was allowed to warm toward ambient temperature and stirred for 6 h. The reaction mixture was poured into ice-water and extracted with CH2Cl2. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford 6.0 g of a mixture of (4-bromo-3,5-dichlorophenyl)methanol and 4-bromo-3,5-dichlorobenzaldehyde—as an off white solid which was taken to next step without purification.
Reaction SMILES: N[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N([O-])=O.[Na+].[BrH:15]>O1CCOCC1.O.[Cu]Br>[Br:15][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
2-Amino-3-fluorobenzonitrile (9.8 g, 71.9 mmol) was dissolved in hot 1,4-dioxane (10 mL), 48% hydrobromic acid (100 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (5.71 g, 82.7 mmol) in water (10 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (31.0 g, 216 mmol) in 48% hydrobromic acid (25 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (600 mL) and extracted with ethyl acetate (2×200 mL). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-3-fluorobenzonitrile (7.05 g, 49%) as a pale brown solid: δH (360 MHz, CDCl3) 7.62-7.68 (1H, m), 7.74-7.85 (1H, ddd, J 9, 9 and 1), 7.74-7.85 (1H, ddd, J 8, 1 and 1).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23]O)=[N:20][C:19]([O:25][CH3:26])=[CH:18][CH:17]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:5]([O:12][C:13]1[C:22]([CH2:23][Br:2])=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([O:25][CH3:26])=[N:20]2)=[N:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc2ncc(OCc3ccccc3)c(CO)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ncc(OCc3ccccc3)c(CBr)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Phosphorus tribromide (32 μL, 0.34 mmol, 2.0 eq) is added at room temperature to a stirred solution of (3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-yl)-methanol (50 mg, 0.17 mmol, 1.0 eq) in dichloromethane (5 mL). After 1 hour stirring at room temperature, pH of the reaction mixture is adjusted to 7 by the addition of a sodium carbonate aqueous solution. The resulting solution is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 7-benzyloxy-8-bromomethyl-2-methoxy-[1,5]naphthyridine as a white solid (62 mg, 99% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:19]\[C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)/[C:10](=[O:11])/[C:12](=[CH:19]/[C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: O=Cc1cccs1
Product: Cc1ccc2c(c1)O/C(=C\c1cccs1)C(=O)/C(=C/c1cccs1)O2

Procedure:
Calone is reacted with thiophene-2-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-thiophen-2-yl-meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)OCc3ccccc3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1)OCc1ccccc1

Procedure:
Example 140 was prepared from diphenylacetyl chloride and benzyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 8: ESMS m/e: 562.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)(=[O:20])=[O:19]>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3cccc(C)c3)c(C)o2)cc1
Agent: Cl
Product: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Yield: 83.2 %

Procedure:
Method C. Reaction of benzoate 31 (217 mg, 0.56 mmol) and 6 M HCl (10 mL) gave acid 32 (173 mg, 83%) as a white solid: mp (H2O) 287-290° C.; 1H NMR δ 13.16 (br s, 1 H, CO2H), 8.05 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.92 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.63 (br s, 1 H, H-2′), 7.54-7.59 (m, 2 H, H-4′, H-6′), 7.50 (t, J=7.6Hz, 1 H, H-5′), 4.65 (s, 2 H, CH2SO2), 2.37 (s, 3 H, CH3), 2.16 (s, 3 H, CH3); MS m/z 372.6 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.74; H, 4.61; N, 3.77. Found: C, 61.51; H, 4.56; N, 3.80%.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([OH:21])[CH2:14][C:15]1[CH:20]=CC=CC=1.N1C=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:23]([O:21][CH2:13][CH2:14][CH2:15][CH3:20])[CH2:24][CH2:25][CH3:26]
Reactant: OCCc1ccccc1
Reactant: c1ccncc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCOCCCC
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a solution of 10.72 g triphosgene in 80 ml dichloromethane, 26.51 g phenethyl alcohol was added. While cooling in an ice bath, 17.16 g pyridine was dropped in over 45 minutes. Then, the reaction was stirred at room temperature for 62 hours. The reaction was diluted with dichloromethane, washed with aqueous HCl and aqueous NaHCO3. The organic phase was dried, filtered and evaporated to dryness. The resulting crystals were recrystallized from 60 ml hexanes and then a second time from hexane:methyl t.-butyl ether (50 ml:50 ml) to yield 15.48 g of colorless crystals.