Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:27])[C:4]2([C:11]3[N:16]=[C:15]4[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]4=[CH:13][CH:12]=3)[CH2:5][CH:6]3[CH:10]([CH:3]12)[CH2:9][NH:8][CH2:7]3.[O:28]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[N:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:27][C:2]1([F:1])[C:4]2([C:11]3[N:16]=[C:15]4[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:14]4=[CH:13][CH:12]=3)[CH2:5][CH:6]3[CH:10]([CH:3]12)[CH2:9][N:8]([C:33]([C:30]1[CH:31]=[CH:32][O:28][N:29]=1)=[O:34])[CH2:7]3
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CNCC5C3C4(F)F)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CN(C(=O)c6ccon6)CC5C3C4(F)F)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(4,4-Difluorooctahydro-4aH-cyclopropa[3,4]cyclopenta[1,2-c]pyrrol-4a-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30-3, 50 mg, 0.14 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 22.5 mg, 0.20 mmol, 1.5 equiv), DIPEA (0.070 mL, 0.40 mmol, 3.0 equiv) and HATU (76 mg, 0.20 mmol, 1.5 equiv) were added to anhydrous acetonitrile (1 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 30-4 as a white solid. MS m/z (M+H): calculated=472.2155; observed=472.2153.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]([CH3:27])[C:15](=[O:26])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([OH:25])[CH3:24])[C:17](=[O:18])[C:12]=2[C:11](=[O:28])[CH:10]=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49](O)(=[O:51])[CH3:50].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:49]([O:25][C@@H:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17](=[O:18])[C:12]2[C:11](=[O:28])[CH:10]=[C:9]([CH3:29])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13]=2[N:14]([CH3:27])[C:15]1=[O:26])(=[O:51])[CH3:50]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2n1Cc1ccccc1
Reactant: CC(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(=O)cc(C)n(Cc3ccccc3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a mixture of (R)-8-benzyl-1,7-dimethyl-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.26 g, 3.18 mmol), triphenylphosphine (2.50 g, 9.52 mmol), acetic acid (0.54 ml, 9.52 mmol) and tetrahydrofuran (20 ml), cooled in an ice bath, was added diethylazodicarboxylate (1.5 ml, 9.5 mmol) dropwise. After stirring at room temperature for 4hours, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-hexanes to afford (S)-3-(5-acetoxyhexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.2 g, 86% yield) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.30-1.75 (m, 6H), 2.02 (s, 3H), 2.49 (s, 3H), 3.67 (s, 3H), 4.03 (t, 2H), 4.88 (sextet, 1H), 5.30 (s, 2H), 6.56 (s, 1H), 7.30-7.56 (m, 5H).
Reaction SMILES: [ClH:1].Cl.[C:3]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:24][C:25]1[N:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH:28]=[N:27][CH:26]=1)(OCC)=[O:4].[Li+].[BH4-]>C1COCC1>[ClH:1].[ClH:1].[OH:4][CH2:3][C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:24][C:25]1[N:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=2)[CH:28]=[N:27][CH:26]=1
Reactant: CCOC(=O)[C@@H]1Cc2ccc(-c3ccccc3)cc2CN1Cc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CN2Cc3cc(-c4ccccc4)ccc3C[C@H]2CO)cc1
Temperature: 50 °C

Procedure:
3(S)-Carboethoxy-7-phenyl-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 0.32 mmol) from Example 21 was dissolved in THF (3 mL) and treated with LiBH4 (13.7 g, 0.64 mmol). The solution was heated at 50° C. for 3 h then quenched with 1N HCl and extracted with EtOAc (3×), washed with brine, dried and evaporated. The residue was purified by preparative HPLC (gradient elution with water/acetonitrile containing 0.1% TFA), the product neutralized and converted to the HCl salt using 1N HCl in ether to give the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([C:14]1[C:20]([C:21]#[N:22])=[C:19]([OH:23])[CH:18]=[CH:17][C:15]=1[OH:16])#[N:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:23][C:19]2[CH:18]=[CH:17][C:15]([O:16][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])=[C:14]([C:12]#[N:13])[C:20]=2[C:21]#[N:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(OS(=O)(=O)c3ccc(C)cc3)c(C#N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
p-Toluenesulfonyl chloride (25.80 g, 135 mmol) was added to a suspension of 2,3-dicyanohydroquinone (10.00 g, 62.5 mmol) and potassium carbonate (34.50 g, 250 mmol) in acetone (75 mL). The temperature of the flask rose rapidly, which stabilised after 2 minutes. The mixture was then heated to reflux and stirred for 2 hours. TLC (eluting: CH2Cl2) indicated that all the starting 2,3-dicyanohydroquinone had been consumed. The mixture was allowed to cool to room temperature, and was poured into water (200 mL), and the mixture stirred for 1 hour. Filtration gave the title compound (Product A) as a colourless solid, which was washed with more water (˜30 mL) and pulled dry. The solid was then dried in an oven (28.36 g, 97%). This material was used without further purification. [Found: C, 55.8%; H, 3.3%; N, 6.0%; S, 13.5%; C22H16O6N2S2 requires C, 56.4%; H, 3.4%; N, 6.0%; S, 13.7%]; MS (EI+) 468 (M+, 80%), 155 (CH3C6H4SO2, 100%), 91 (CH3C6H4, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[C:16]3[CH:17]=[C:18]([F:27])[CH:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]=3[N:14]=[CH:13]1)[C:6]([CH3:28])=[C:5]2[C:29]([O:31]C)=[O:30].BrC1C(C)=C(C(OC)=O)C2C(=CC=C(F)C=2)N=1>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[C:16]3[CH:17]=[C:18]([F:27])[CH:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]=3[N:14]=[CH:13]1)[C:6]([CH3:28])=[C:5]2[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1c(C)c(-n2cnc3c(-c4ccccc4)cc(F)cc32)nc2ccc(F)cc12
Agent: COC(=O)c1c(C)c(Br)nc2ccc(F)cc12
Solvent: CCCCO
Product: Cc1c(-n2cnc3c(-c4ccccc4)cc(F)cc32)nc2ccc(F)cc2c1C(=O)O
Temperature: 25 °C
Yield: 3.7 %

Procedure:
Methyl 6-fluoro-3-methyl-2-(6-fluoro-4-phenyl-1-benzimidazolyl)quinoline-4-carboxylate: A mixture of 2-bromo-4-carbomethoxy-6-fluoro-3-methylquinoline, obtained in Example 1D, (2.53 g, 8.48 mmol) and the product of example 68C (1.80 g, 8.48 mmol) in n-butanol (12 mL) was heated at reflux for 18 h. The reaction was allowed to cool to room temperature and solvent was removed. The residue was chromatographed (1:1 hexanes-ethyl acetate) to provide the desired product (0.135 g, 0.31 mmol) in 3.7% yield as a tan solid, mp=208°-210° C.; NMR(CDCl3): 8.27 (s, 1H), 8.13 (dd, 1H), 8.01 (d, 2H), 7.41-7.62 (m, 5H), 7.30 (dd, 1H), 7.06 (dd, 1H), 4.16 (s, 3H), 2.40 (s, 3H); IR(KBr): 1734; Mass spectrum: m/z 430.0 (M+H).
Reaction SMILES: [CH2:1]([C@@H:5]1[NH:11][C@H:10]([CH3:12])[CH2:9][CH2:8][N:7]([C@@H:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:14]([NH2:16])=[O:15])[C:6]1=[O:28])[CH:2]([CH3:4])[CH3:3].[N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH2:39][C:40](O)=[O:41])=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C@@H:5]1[N:11]([C:40](=[O:41])[CH2:39][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:29]=[CH:30][CH:31]=[CH:32]3)[C@H:10]([CH3:12])[CH2:9][CH2:8][N:7]([C@@H:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:14]([NH2:16])=[O:15])[C:6]1=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H]1N[C@H](C)CCN([C@@H](Cc2ccc3ccccc3c2)C(N)=O)C1=O
Reactant: O=C(O)Cc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(N)=O)CC[C@@H](C)N1C(=O)Cc1ccc2ncccc2c1

Procedure:
(S)-2-[(3S,5R)-3-isobutyl-5-methyl-2-oxo-[1,4]diazepan-1-yl]-3-(naphthalen-2-yl)-propionamide (382 mg, 1 mmol) is added to a solution of 6-quinolylacetic acid (372 mg, 2 mmol), Hünig's base (170 μl, 1 mmol) and EADC (383 mg, 2 mmol) in CH2Cl2 (50 ml). After 16 hours at RT the reaction mixture is extracted with 0.1 N HCl and then with 5% NaHCO3 solution. Pure title compound is isolated after silica gel chromatography using ethyl acetate —>ethyl acetate/MeOH (9/1) as mobile phase. MH+:551.4 (ESI) αD20=−12.5° (c=0.12 95% AcOH)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)=[CH:4][C:3]=1[F:17].CCN(CC)CC.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[Si:25]([O:14][CH2:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH2:1])=[C:3]([F:17])[CH:4]=2)[CH:12]=[CH:11][N:10]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: Nc1ccc(Oc2ccnc(CO)c2)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A solution of (4-(4-amino-3-fluorophenoxy)pyridin-2-yl)methanol (750 mg, 3.2 mmol) and Et3N (821 mg, 8 mmol) in DMF (10 ml) at 0° C. was treated with tert-butyldimethylsilyl chloride (624 mg, 4.16 mmol). The resulting solution was stirred at RT for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to provide 4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorobenzenamine (370 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=5.6 Hz, 1H), 7.02 (s, 1H), 6.67-6.82 (m, 4H), 4.76 (s, 2H), 3.71 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H); MS (ESI) m/z: 349.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: NC(N)=O
Reactant: COc1cccc(C=O)c1N
Product: COc1cccc2cnc(O)nc12
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Solid 2-amino-3-methoxybenzaldehyde (37.2 g, 0.246 mole), urea (158 g, 2.5 mole) and catalytic NH4OAc (1 g) were thoroughly mixed together in a roundbottom flask. The solid mixture was heated in a 160° C. bath. The solids quickly melted and stirring was commenced. After about 15 minutes, solids start to precipitate from the hot solution. After adding NMP (150 mL) to dissolve the solids, the reaction was heated with stirring for an additional 30-45 minutes until complete as judged by LCMS. The hot reaction mixture was poured into vigorously stirred water (400 mL). The reaction flask was washed out with water (3×100 mL) and EtOAc (4×50 mL). After stirring ca. 30 minutes, mixture was filtered to collect the light solid precipitate. The solid filter cake was washed with portions of water and EtOAc to give a white solid. The solid was dried on the frit and in vacuo to give the product in 99% purity and 95% yield (41 g, 233 mmole).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:28]([CH3:30])[CH3:29])[C:7]([N:9]1[C@H:17]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:28]([CH3:30])[CH3:29])[C:7]([N:9]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OCc1ccccc1)OCCO2)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)O)OCCO2)C(C)C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
(S)-benzyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate (2.3 g, 5.47 mmol) was dissolved in ethyl alcohol (55 mL) and under Argon charged with 10% Pd/C in a round bottom flask. The flask was then sealed with a rubber septa and the air was removed by vacuum and replaced with H2 from a balloon. This process repeated three times and the mixture was stirred under H2 atmosphere for 18 hours. The resulting mixture was then passed through a elite plug and concentrated down on rotovap to yield 1.76 g, 98% desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[S:12]1[CH:16]=[CH:15][C:14]([Li])=[CH:13]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:14]1[CH:15]=[CH:16][S:12][CH:13]=1)([OH:11])[CH3:10]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: [Li]c1ccsc1
Product: CC(O)(c1ccsc1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and 3-thienyllithium generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.43 (dd, J=2.98, 4.98 Hz, 1H), 7.33 (dd, J=1.27, 2.94 Hz, 1H), 7.07 (dd, J=2.37, 8.47 Hz, 1H), 7.04 (d, J=2.33 Hz, 1H), 6.92 (dd, J=1.26, 4.98 Hz, 1H), 6.52 (d, J=8.38 Hz, 1H), 5.99 (bs, 1H), 5.32 (bs, 2H), 1.78 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:20])[C:18]=1[OH:19])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6].[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:20][C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([CH3:1])[C:18]=1[O:19][CH3:21])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=[O:6]
Reactant: Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1C
Yield: 94.3 %

Procedure:
A solution containing compound 1 (15.0 g, 55.4 mmol), K2CO3 (20.0 g, 0.145 mol) and CH3I (30 mL, 0.48 mol) in 250 mL acetone was refluxed for 6 hours. The solvent was evaporated and the residue partitioned between CH2Cl2 and H2O. The organic layer was dried over Na2SO4, filtered and evaporated to leave a yellow-white powder. Recrystallization from CH3OH/pet ether at -20° C. gave 14.9 g of white crystals (94%). The material was characterized by NMR, TLC, mass spectroscopy, IR and elemental analysis, m.p. 131°-132.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl.N1C=CC=CC=1.ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: COC(CNCc1ccc(F)c(Cl)c1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
147.0 g (3-Chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 540 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 145.8 g (1.04 mol) p-toluenesulfonylchloride in 200 ml of dichloromethane was added. After 5 h at room temperature additional 20 ml of pyridine, 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added. The solution was stirred at room temperature for 7 h and then refluxed for additional 4 h. Again 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added and the mixture was stirred overnight. For workup, the solution was washed twice with 2 N HCl and twice with saturated NaHCO3-solution. The organic layer was dried with MgSO4 and evaporated. Final silica gel chromatography (heptane/ethyl acetate 4:1) gave 155 g of the title compound as a yellow oil. Rt=1.80 min (Method B). Detected mass: 370.2 (M-OMe−).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=[O:7])C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH2:23][CH2:22][CH2:21]2.[OH-].[Na+].C>O>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:25]3[N:24]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=1
Reactant: COc1ccc2c(c1)CCCN2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c3c(c1)c(=O)c(C(=O)O)cn3CCC2
Temperature: 220 °C
Reaction time: 1 h

Procedure:
Diethyl ethoxymethylenemalonate (43.2 g., 0.20 mole) and 6-methoxytetrahydroquinoline (32.6 g., 0.20 mole) are mixed and heated at 125°-130° C. for 3 hours. Polyphosphoric acid (200 g.) is as added, and the mixture is heated gradually to 220° C. then maintained at 220° c. for 1 hour. The mixture containing the product ester of Formula III is poured into about 600 ml. of water, then made basic with 40 percent sodium hydroxide solution and heated on a steam bath for two hours. The solution is treated with decolorizing charcoal, filtered and acidified. The solid product is isolated by filtration, washed with water and ethanol, then recrystallized from N,N-dimethylformamide to give 6,7-dihydro-9-methoxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 253°-257° C.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1)([O-:3])=[O:2].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N+:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:9]=1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])Cc1cn[nH]c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])Cc1cnn(C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 430 mg of 4-(nitromethyl)-1H-pyrazole in 4.3 ml of ethyl acetate were added 0.62 ml of 3,4-dihydro-2H-pyran and 129 mg of 4-methylbenzenesulfonic acid monohydrate, followed by stirring at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 213 mg of 4-(nitromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)(=O)=O.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:30]2[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]2)[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A solution of 2-methyl-5-quinolinyl trifluoromethanesulfonate (1 wt, 1 eq) in toluene (7 vol) was degassed under reduced pressure then flushed with nitrogen. To the mixture were added N-Boc-piperazine (1.05 eq), milled cesium carbonate (1.5 eq), (+/−)-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 0.15 eq) and palladium acetate (0.05 eq). The resulting mixture was stirred at 95° C. for 16 hours. The solution was cooled and concentrated to approx. 4 vol and 10 vol of cyclohexane were added giving a suspension. The suspension was stirred for 30 minutes and filtered over a pad of Silica Gel (approx 2.5 vol). The filtrate was washed with 10 vol of water and concentrated under reduced pressure to give the title compound as a brown solid, which was carried through directly to the next stage.
Reaction SMILES: C([NH:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[S:29](=[O:38])(=[O:37])[CH2:28][CH2:27]3)[N:16]=2)[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[S:29](=[O:38])(=[O:37])[CH2:28][CH2:27]3)[N:16]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC3(NCc4ccccc4)CCC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC3(N)CCC3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
A mixture of N-[(1-benzylamino-cyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (220 mg, 0.417 mmol), 10% of palladium hydroxide on carbon (30 mg), and trifluoroacetic acid (160 μL) in methanol (20 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was adjusted to pH 8-9 by the addition of a solution of ammonia in methanol (7 M), and concentrated in vacuo. The residue was purified by preparative HPLC to give 105 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=7.6 Hz, 1 H), 7.86 (d, J=7.6 Hz, 1 H), 7.73 (s, 1 H), 7.60 (t, J=7.6 Hz, 1 H), 7.47-7.32 (m, 3 H), 5.33 (s, 2 H), 4.58 (brs, 2 H), 3.84 (s, 2 H), 3.53 (t, J=4.8 Hz, 2 H), 2.41 (s, 3 H), 2.21 (m, 2 H), 2.04-1.97 (m, 2 H), 1.91-1.82 (m, 2 H).
Reaction SMILES: FC(F)(F)S(O[CH2:7]/[CH:8]=[C:9]1/[CH:10]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[O:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]/1)(=O)=O.[O:32]1CCOCC1.CO.[OH-].[Na+]>[Cl-].[Na+].O.C(OC(=O)C)C>[N+:27]([C:24]1[CH:23]=[CH:22][C:21]([C@H:10]2[C@@H:9]([CH:8]([OH:32])[CH3:7])[CH2:14][CH2:13][C@@H:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:11]2)=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(C2OC(c3ccccc3)CC/C2=C\COS(=O)(=O)C(F)(F)F)cc1
Reactant: C1COCCO1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)[C@H]1CC[C@@H](c2ccccc2)O[C@H]1c1ccc([N+](=O)[O-])cc1
Yield: 75 %

Procedure:
A solution of (E)-(2-(4-nitrophenyl)-6-phenyl-dihydro-2H-pyran-3(4H)-ylidene)ethyl trifluoromethanesulfonate (0.3 mmol) in a mixture of 2:1 1,4-dioxane:methanol was treated with an aqueous NaOH solution (1%, 4 mL) at room temperature for 3 hours with stirring. Following completion of the reaction, brine was added to the reaction solution which was then diluted with ethylacetate. The organic layer thus formed was washed with water, dried over Na2SO4, filtered and concentrated. The purification of the concentrate afforded the title compound (Yield 75%).