Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+].[CH3:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([N+:34]([O-:36])=[O:35])[CH:26]=1)(=[O:24])=[O:23].O=C1C2CC(CC2)C(OC(=O)C2C=CC(S(C)(=O)=O)=CC=2[N+]([O-])=O)=C1>C(#N)C.C(OCC)(=O)C>[OH:3][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:1]=1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][C:27]=1[N+:34]([O-:36])=[O:35]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: C=C1OC(=O)C2CCC1C2
Agent: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)C3CCC2C3)c([N+](=O)[O-])c1
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)C2=C(O)C3CCC(C3)C2=O)c([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
2.76 g (0.02 mol) of 93% 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 4.45 g (0.044 mmol) of triethylamine are stirred for 7 hours at room temperature in 50 ml of acetonitrile in the presence of 130 mg (2 mmol) of potassium cyanide. 4.22 g (0.16 mol) of freshly prepared 4-methanesulfonyl-2-nitrobenzoyl chloride are then introduced and stirring is carried out for 12 hours at a temperature of 20° C. If, according to monitoring by thin-layer chromatography, relatively large amounts of the intermediate 4-methanesulfonyl-2-nitrobenzoic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (known from U.S. Pat. No. 5,801,120) are still detectable, then a further 130 mg (2 mmol) of potassium cyanide are added and stirring is continued for a further 2 hours until conversion is complete. The reaction mixture is then taken up in ethyl acetate and extracted at a pH value of 13 against water. The aqueous phase is then acidified using hydrochloric acid and extracted at a pH value of approximately 4 using fresh ethyl acetate, dried over Na2SO4 and concentrated to a slight extent. The product, dissolved in warm ethyl acetate, is treated with activated carbon and filtered off with suction (suction filter) through a small amount of silica gel, then concentrated further and caused to crystallise by adding a small amount of hexane. 1.69 g of pure 4-hydroxy-3-(4-methanesulfonyl-2-nitrobenzoyl)-bicyclo[3.2.1]oct-3-en-2-one having a melting point of 170–170.5° C. are obtained. Further product (1.65 g) can be obtained from the mother liquor by recrystallisation. Total yield: 3.34 g, or 49.1% based on the starting material 4-methylene-3-oxabicyclo[3.2.1]octan-2-one used or 57.1% based on the starting material 4-methanesulfonyl-2-nitrobenzoic acid used. 1H-NMR (CDCl3): 15.94 ppm, s, 1H, 8.74, s, 1H, 8.24 ppm, d, 1H, 7.48 ppm, d, 1H, 3.20 ppm, m, 1H, 3.19 ppm, s, 3H, 2.84 ppm, m, 1H, 2.0–2.3 ppm, 4H, 1.6–1.8 ppm, 2H.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([C:25]([O:27]CC)=[O:26])[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:19]=2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32])#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([C:25]([OH:27])=[O:26])[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[CH:19]=2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32])#[N:2]
Reactant: CCOC(=O)c1cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cc(C(=O)O)cc(C(=O)O)c2)c1F
Temperature: 60 °C

Procedure:
To 5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylic acid, diethyl ester (0.97 g, 2.0 mmol) in tetrahydrofuran/water (20 mL, 1/1) was added lithium hydroxide (0.42 g, 10 mmol). After heating at 60° C. for 90 minutes, the material was partitioned between ethyl acetate and 2N HCl. The organic layer was separated, dried (MgSO4), and the solvent removed in vacuo to give 5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylic acid; NMR (DMSO) 8.25 (s,1), 7.85 (s,2), 7.4-7.7 (m,3), 7.3 (m,3), 2.4 (s,3) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])([O-])=O.O>CO.[Ni].C1(C)C(C)=CC=CC=1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:12]3[CH:13]=[CH:19][CH:18]=[CH:17][C:16]=3[C:14](=[O:15])[NH:1][C:4]=2[CH:9]=1
Reactant: O=C(Oc1ccc(Cl)cc1[N+](=O)[O-])c1ccccc1O
Agent: [Ni]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reaction time: 20 h
Yield: 47.1 %

Procedure:
A solution of 33.74 g of O-(2-nitro-4-chlorophenyl)salicylic acid in 150 mL of methanol was hydrogenated over Raney nickel (6.8 g) at room temperature and 30 psi pressure with stirring for 20 hours. The crude amino acid obtained on evaporation of the methanol was refluxed in 150 mL of xylene for 20 hours with continuous removal of water. The xylene solution was cooled and the xylene was removed, the residue was washed with THF, filtered and dried to provide 8-chloro-10H-dibenzo[b,f][1,4]oxazepin-11-one as gray solid (13.3 g, 40%), mp 260-261°. 1H NMR (300 MHz, DMSO-d6), δ 7.15-7.2 (m, 2H), 7.3-7.4 (m, 3H), 7.64 (ddd, 1H, J=1.9, 7.8 and 8.4 Hz), 7.78 (dd, 1H, J=1.5 and 7.7 Hz), 10.589 (s, 1H, —NH).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[CH:14]([OH:16])C.[C:18]1(C=CC(O)=CC=1)[OH:19]>[Cl-].[Cl-].[Zn+2].C(O)C>[C:4]([O:6][CH2:7][CH2:8][CH2:18][OH:19])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:10][CH2:11][CH2:12][CH2:14][OH:16])=[O:9]
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: CC(O)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: O=C(/C=C/C(=O)OCCCO)OCCCO

Procedure:
Poly(propylene fumarate) was synthesized following a two step procedure [11]. First, 1 mole of diethyl fumarate (Acros Organics, Pittsburgh, Pa.) and 3 moles of 1,2 propanediol (Acros Organics) were reacted using 0.01 moles ZnCl2 (Fisher Chemicals, Fair Lawn, N.J.) as a catalyst and 0.002 moles hydroquinone (Acros Organics) as a radical inhibitor. The reaction was run under a nitrogen blanket, producing bis(hydroxypropyl) fumarate as the main product and ethanol as a byproduct. Second, the bis(hydroxypropyl) fumarate was transesterified, producing poly(propylene fumarate) and 1,2 propanediol as a byproduct.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:38][C@@H:39]1[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([C:48]2[O:52][N:51]=[C:50]([CH2:53][CH3:54])[N:49]=2)[O:41][C@@H:40]1OC(=O)C)(=[O:37])[CH3:36].C(O[C@@H]1[C@H](OC(=O)C)[C@@H](C2ON=C(CC)N=2)O[C@H]1OC(=O)C)(=O)C>>[C:35]([O:38][C@@H:39]1[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([C:48]2[O:52][N:51]=[C:50]([CH2:53][CH3:54])[N:49]=2)[O:41][C@H:40]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=2[NH:10][CH2:9][CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:37])[CH3:36]
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCc1noc([C@H]2O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: CCc1noc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: Cl
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and a mixture of (2R,3R,4R,5S)-2,4-bis(acetoxy)-5-(3-ethyl-1,2,4-oxadiazol-5-yl)tetrahydro-3-furanyl acetate and (2S,3R,4R,5S)-2,4-bis(acetoxy)-5-(3-ethyl-1,2,4-oxadiazol-5-yl)tetrahydro-3-furanyl acetate (Preparation 14).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22](O)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1.O.[NH3:27]>ClCCl>[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22]([NH2:27])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: N
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 50 °C
Yield: 69.8 %

Procedure:
Oxalyl chloride (0.04 g, 0.3 mmol) was slowly added to a solution of 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture was warmed to 50° C. for 4 hr and then cooled to 25° C. The solution was condensed in vacuum and then slowly added to 28% ammonia water (10 mL) and a solid precipitated out immediately. The mixture was warmed to 50° C. and stirred for another 2 hr. Water (20 mL) was added to the mixture and the slurry was cooled to 25° C. The product was filtered and the cake was washed with water, dried to afford 44 mg 2-p-tolylbenzo[d]oxazole-4-carboxamide as a solid (yield 69.8%). 1H-NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 6.01 (s, 1H), 7.34-7.36 (d, J=7.6 Hz, 2H), 7.43-7.47 (t, J=8.0 Hz, 1H), 7.71-7.73 (d, J=8.0 Hz, 1H), 8.15-8.18 (m, 3H), 9.02 (s, 1H); LC-MS (ESI) m/z 253 [M+1]+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.[OH2:24]>>[NH2:13][C:14]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:1][C:11]2[C:6]([C:4]=1[C:2]([OH:24])=[O:3])=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Product: Nc1c(-c2ccc(Cl)cc2)nc2ccccc2c1C(=O)O

Procedure:
A solution of 5.8 g of isatin in water was reacted with 12.0 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride by the procedure described in example 33, giving 8.1 g of the desired compound as a yellow solid, mp 243°-244° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[OH:3][CH:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1ccc2ccccc2n1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(O)C1CCc2ccccc2N1
Yield: 77.3 %

Procedure:
2-Acetylquinoline (21.0 g, 0.123 mol) in acetic acid (210 mL) was hydrogenated over platinum oxide (1.0 g) under atmospheric pressure of hydrogen at room temperature until the theoretical amount of hydrogen was consumed. The mixture was passed through celite and concentrated. The residue was purified by column chromatography with 5:1 to 1:1 hexane/ethyl acetate to give 16.85 g of 2-(1-hydroxyethyl)tetrahydroquinoline (78%): 1H NMR (270 MHz, CDCl3) δ6.95 (m, 2H), 6.62 (td, 1H, J=7.3, 1 Hz), 6.51 (dd, 1H, J=7.3, 1 Hz), 3.81 (dq, 1H, J=10.2, 6.6 Hz), 1.87 (m, 1H), 1.76 (m, 1H), 1.20 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:23]([CH3:22])(=[O:25])=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(C)(=O)=O

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine was reacted with methanesulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-methanesulfonamide as a colorless solid. MS: 419.3 ([M+NH4]+)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 109.3 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2,4-difluorophenyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example J-4, 0.20 g, 0.45 mmol) and triethylamine (0.34 mL, 2.4 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 6 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.23 g of the title compound as a solid, mp 212-214° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:8][C:7]2=[O:19])([O-])=O.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([S:28]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:7]3=[O:19])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]
Reactant: O=c1[nH]n(-c2ccccc2)c2ccc([N+](=O)[O-])cc12
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: N#Cc1cccc(S(=O)(=O)Nc2ccc3c(c2)c(=O)[nH]n3-c2ccccc2)c1

Procedure:
This compound was obtained in analogy to example 32 (step B and C) using 5-nitro-1-phenyl-1,2-dihydro-indazol-3-one (prepared according to Combinatorial Chemistry and High Throughput Screening 2003, 6(5), 471-480) in step B and 3-cyanobenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI+): 391.1[M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26]C)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a stirred solution of methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylate (0.06 g, 0.139 mmol) in 5 mL of THF and 5 mL of methanol was added a solution of NaOH (0.056 g, 1.39 mmol) in 1 mL of water at room temperature. After the addition, the reaction was stirred at this temperature for 24 hours. The solvent was evaporated and the residue was suspended in 10 mL of THF, then treated by HCl until pH=2. The solvent was evaporated and then dissolved in 30 mL of THF, filtered. The filtrate was evaporated to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (0.057 g, 98%) as a solid. LC-MS: 416.1 [M+H]+, tR=1.57 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22](N)[CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CC[N:43](CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:43][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[OH:24])=[CH:18][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(O)Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 0.26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH:10]=[C:9](OCC)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C1(N)C(F)=C(F)C(F)=C([NH2:35])C=1F.Cl.Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][C:9]2=[N:35][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:18]([CH3:17])=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC=C(OCC)CC1
Reactant: NCC(=O)c1ccccc1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CCOC(=O)N1CCCc2nc3ccccc3c(C)c2C1

Procedure:
2,3,4,5-tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester and their hydrochlorides were prepared from an isomer mixture of 1-ethoxycarbonyl-4-ethoxy-2,3,6,7-tetrahydro-azepine and 1-ethoxycarbonyl-4-ethoxy-5H-1,2,6,7tetrahydro-azepine (ratio: 1:1) and 2-amino-acetophenone analogous to Example 217. Yield of the dihydrochloride of the [4,5-b]-isomer: 52% of theory; m.p. 247° C. Yield of the dihydrochloride of the [4,3-b]-isomer: 43% of theory; m.p. 219° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[C@@H:19]([CH3:21])[CH2:18][C:17]([O:24][CH3:25])([O:22][CH3:23])[C@@H:16]3[OH:26])[CH:13]=[C:12]([O:27][CH3:28])[CH:11]=[CH:10]2)(=O)=O.C(N(CC)CC)C.C(O)=O>O1CCOCC1>[CH3:28][O:27][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[C:15]3[C:20](=[CH:7][N:8]=2)[C@@H:19]([CH3:21])[CH2:18][C:17]([O:22][CH3:23])([O:24][CH3:25])[C@@H:16]3[OH:26])[CH:13]=1
Reactant: COc1ccc2nc(OS(=O)(=O)C(F)(F)F)c3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2ncc3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Temperature: 23 °C
Yield: 96.9 %

Procedure:
Tetrakistriphenylphosphine palladium (778 mg, 673 mmol, 0.04 equiv) was added to a deoxygenated solution of (7S,10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-6,10-phenanthridinediol 6-(trifluoromethanesulfonate) (13, 7.60 g, 16.8 mmol, 1 equiv) and triethylamine (9.40 mL, 67.3 mmol, 4.00 equiv) in dioxane (300 mL) at 23° C. The resulting solution was deoxygenated by alternately evacuating the reaction vessel and flushing with argon (5×). Formic acid (1.70 mL,. 43.8 mmol, 2.63 equiv) was added slowly over 5 min via syringe and the resulting solution was heated at reflux for 20 min, then was allowed to cool to 23° C. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (300 mL) and ethyl acetate (300 mL). The aqueous layer was separated and further extracted with ethyl acetate (2×300 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (ether initially, grading to 20% ethyl acetate-ether) to provide (7S,10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-10-phenanthridinol (15) as a white foam (mp 135°-136° C., 4.94 g, 97%). ##STR25##
Reaction SMILES: FC(F)(F)C1C=CC(N2C=NC(C3C=CC(C[CH2:21][C:22](N=[N+]=[N-])=[O:23])=CC=3)=N2)=CC=1.[N:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=3)[N:41]=2)=[CH:36][CH:35]=1)=[C:30]=[O:31].[CH:55]([C:58]1[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][C:59]=1[NH:65][C:66]([NH2:68])=[S:67])([CH3:57])[CH3:56]>>[CH:55]([C:58]1[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][C:59]=1[N:65]1[C:22](=[O:23])[CH2:21][S:67]/[C:66]/1=[N:68]\[C:30]([NH:29][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=3)[N:41]=2)=[CH:36][CH:35]=1)=[O:31])([CH3:57])[CH3:56]
Reactant: [N-]=[N+]=NC(=O)CCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: O=C=NCCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(C(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 35 using 3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoyl azide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C35b) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as a tan glassy foam (0.132 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH2:10][C:11]#[N:12].[NH2:14][NH2:15]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([NH2:12])[NH:14][N:15]=1
Reactant: COc1ccccc1C(=O)CC#N
Reactant: NN
Solvent: CCO
Product: COc1ccccc1-c1cc(N)[nH]n1

Procedure:
3-(2-Methoxy-phenyl)-3-oxo-propionitrile (2.4954 gms.) is then suspended in 55 mL of anhydrous EtOH. This suspension is treated with 0.90 mL of anhydrous hydrazine and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(Cl)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH:48][C:24]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:12][N:8]1[C:6](=[O:7])[CH:33]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:26])[CH3:44]
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOCc2ccc(OC)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 56% purity by LC/MS. MS(ESI+): m/z=557.4.