Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[CH3:29][O:30][C:31]([NH:33][C:34](=NC(OC)=O)SC)=[O:32]>C(O)(=O)C.C(OCC)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[NH:28][C:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])=[N:27][C:24]5=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c(N)c4)cc3C2)CC1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(C)CC3)CCO4)cc2[nH]1
Temperature: 80 °C
Yield: 11.7 %

Procedure:
To a solution of 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (0.21 g, 0.55 mmol) in acetic acid (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.17 g, 0.82 mmol) and the resulting mixture was heated at 80° C. After 12 h the reaction mixture was diluted with ethyl ether (5 mL) and the resulting precipitate was collected by filtration. The resulting brown filter cake was dissolved in methanol and purified by preparative reverse phase HPLC to afford methyl (6-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.030 g, 12% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): 12.02 (bs, 1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.38-7.55 (m, 2H), 6.96-7.06 (m, 1H), 4.36-4.44 (m, 2H), 4.06-4.22 (m, 2H), 3.76 (s, 3H), 3.44-3.60 (m, 4H), 2.68 (t, 2H) 1.43-1.61 (m, 3H), 1.20 (q, 2H), 0.90 (d, 3H); MS (EI) for C24H28N6O4: 465 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][NH:13][S:14]([CH2:17][Cl:18])(=[O:16])=[O:15].C(N(CC)CC)C>C(OCC)C>[CH3:12][N:13]([S:14]([CH2:17][Cl:18])(=[O:16])=[O:15])[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: CNS(=O)(=O)CCl
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(=O)(=O)CCl
Temperature: 20 °C
Yield: 64.1 %

Procedure:
A solution of 19 g of 3,4-dichlorophenyl isocyanate in 150 ml of ethyl ether was added to a solution of 14.4 g of N-methyl-N-chloromethylsulfonyl-amine in 150 ml of ethyl ether and after the addition of 0.1 ml of triethylamine, the mixture was stirred for a hour at 20° C. The crystals formed were recovered by vacuum filtration, were washed, dried and dissolved in chloroform. The insolubles were removed by filtration and the filtrate was concentrated to dryness. The product was crystallized from methyl ethyl ketone to obtain 21.3 g of N-methyl-N-chloromethylsulfonyl-N'-(3,4-dichlorophenyl)-urea melting at 119° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc([N+](=O)[O-])c1)C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(3-nitrophenyl)propanoic acid (562 mg, 1.8 mmol) in THF (9 ml) stirred at 0° C. under N2 atmosphere, 10 M solution of BH3.DMS (0.5 ml, 5.27 mmol) was slowly added, after addition was completed the final mixture was warmed to room temperature and stirred for further 6 h. Cooled down to 0° C., quenched with water, diluted with DCM and washed with 10% K2CO3 solution in water; dried over MgSO4, filtered and concentrated to afford 432mg (80% yield) of an oil which was submitted to the next step without further purification. MS: m/z=319.1 (MH+)
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:38]1[CH:43]=[C:42]([O:44]C)[C:41]([O:46]CC2C=CC=CC=2)=[C:40]([O:54]C)[CH:39]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.O>ClCCl>[OH:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:38]1[CH:43]=[C:42]([OH:44])[C:41]([OH:46])=[C:40]([OH:54])[CH:39]=1
Reactant: CCCCCCCCCCCCCCCCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirring solution of 40j (0.455 g, 0.6 mmol) in dichloromethane (25 ml) under Ar at 0° C. was added boron tribromide in dichloromethane (1.0M, 6 ml, 6 mmol, 9.8 equ). The mixture was warmed to room temperature and then stirred for 22 hours. The reaction was then cooled to 0° C. and methanol (25 ml) added. The reaction was heated to reflux for 2 hours, then concentrated in vacuo to give a yellow solid. Water (50 ml) was added and sonicated then left to stand overnight then 9j (0.325 g, 99%) was collected as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[P:20]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:21]Cl>O1CCCC1>[C:8]([CH:1]([P:20](=[O:21])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOP(OCl)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C#N)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred solution of benzyl cyanide (2.5 g) in dry tetrahydrofuran (25 mL), slowly added lithium hexamethyl disilazane (26 mL, 1.0M in THF) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 1 hour and chloro diethyl phosphite (5 g) was added slowly under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for about 2 hours and quenched with saturated ammonium chloride solution (25 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure gave crude diethyl cyano(phenyl)methylphosphonate (3 g) as yellow liquid, which was used without any purification. 1H NMR (CDCl3): δ 1.24-1.28 (t, 3H), 1.30-1.33 (t, 3H), 4.14-3.90 (m, 4H), 4.20 (d, 1H), δ 7.45-7.20 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:23]([CH2:24][CH:18]([C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])[CH2:19][C:20]([OH:22])=[O:21])[NH:9][C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=C1CC(c2ccc(Cl)cc2Cl)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1Cl

Procedure:
By a procedure similar to that of example 1.4, starting from 4-chloro-1,2-phenylenediamine and 3-(2,4-dichlorophenyl)glutaric anhydride, 4-(5-chloro-2-benzimidazolyl)-3-(2,4-dichlorophenyl)butanoic acid•HCl was obtained as light greyish solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:35]([O:37][CH:38]([O:45][CH2:46][CH3:47])[C:39]#[C:40][C:41]([O:43][CH3:44])=[O:42])[CH3:36]>C1COCC1.O>[CH2:46]([O:45][CH:38]([O:37][CH2:35][CH3:36])/[C:39](/[O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])[CH3:47]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(C#CC(=O)OC)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of 2.79 g (15 mmol) of 4-phenoxyphenol in 40 mL of THF was added 1.14 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.72 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetate-hexane yielded 3.02 g (55%) of an oil, used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[N:14]=[C:13](O)[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:17]=1.N1C2C3C=CC=CC=3CCC=2C=NC=1O.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:13]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[C:15]=2[N:14]=1
Reactant: COc1ccc2c(c1)CCc1cnc(O)nc1-2
Reactant: O=P(Cl)(Cl)Cl
Agent: Oc1ncc2c(n1)-c1ccccc1CC2
Product: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Temperature: 100 °C
Yield: 86 %

Procedure:
A suspension of 8-Methoxy-5,6-dihydro-benzo[h]quinazolin-2-ol as a 1:1 urea complex from preparation 1 (20 g, 69.0 mM) in POCl3 (350 ml) was heated under nitrogen atmosphere at 100° C. for 20 hr. The POCl3 was removed under reduced pressure and the residue was suspended in dichloromethane (300 ml) and cooled in an ice bath and then concentrated sodium bicarbonate (500 ml) was carefully added followed by 1 N NaOH (200 ml) and the phases separated. The aqueous phase was extracted with dichloromethane (3×500 ml) and the pooled organic phases were dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure to give 2-Chloro-8-methoxy-5,6-dihydro-benzo[h]quinazoline (2, 14.46 g, 86% yield) as a yellow solid. ES-MS MH+ 247.1. 1H NMR (300 MHz, ppm, DMSO-d6): 8.54 (s, 1H), 8.09 (d, 1H), 6.99 (m, 3H) 3.84 (s, 3H), 2.91 (m, 4H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[C:40](/[CH2:46]N2C=CC=N2)=[CH:41]\[C:42](OC)=[O:43])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])/[CH:41]=[C:40](/[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)\[CH3:46])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reactant: COC(=O)/C=C(/Cn1cccn1)c1cccc(C#N)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (105 mg, 0.34 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.5 ml, 1.02 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of methyl (E)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (90 mg, 0.34 mmol) in 1 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 20 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate, filtered and concentrated to give (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (155 mg, 85%) as an off-white foam which was sufficiently pure to be used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[N+:7]([O-])=O.[C:11](OC(=O)C)(=[O:13])[CH3:12]>[Fe]>[Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[NH:7][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Br)sc1Br
Agent: [Fe]
Product: CC(=O)Nc1cc(Br)sc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To an ice cold solution of 2,5-dibromo-3-nitrothiophene (5.0 g, 17.4 mmol, DellErba, C.; Spinelli, D. Tetrahedron, 1965, 21, 1061-1066) in acetic acid-acetic anhydride (1:1, 50 mL) was added iron powder (5.8 g, 104.5 mmol) slowly for 15 min. and stirred at rt for 4 h. After completion of the reaction, the reaction mixture was poured into ice cold water (500 mL) and stirred for 15 min. The precipitated solid was filtered, washed with water and dried. The crude product was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluent to give the product as a white color solid (3.0 g, 58%), mp 114-116° C. 1H NMR (400 MHz, CDCl3): δ 7.78 (1H, s), 7.21 (1H, s), 2.20 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[CH3:20][C:21]1[CH2:26][O:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N(Cl)C(=O)C1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:27]([CH:24]1[CH2:23][CH:22]=[C:21]([CH3:20])[CH2:26][O:25]1)=[O:28])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: CC1=CCC(C(=O)O)OC1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CC=C(C)CO1)C(C)C
Yield: 65.3 %

Procedure:
The coupling of 3-isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (63.3 mg, 0.23 mmol) and 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (40 mg, 0.28 mmol) using PPh3 (78.6 mg, 0.3 mmol) and NCS (39.9 mg, 0.3 mmol) furnished 3-[isopropyl-(5-methyl-3,6-dihydro-2H-pyran-2-carbonyl) -amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (60 mg, 65.3% yield). NMR 1H (CDCl3, 400 MHz, for major rotamer): 7.68-7.62 (m, 2H), 7.4-7.5 (m, 3H), 7.22 (s, 1H), 5.46 (m, 1H), 3.86 (s, 3H), 1.48 (s, 3H), 1.24 (d, 3H), 1.0 (d, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.O1CCOCC1>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2ccccn2)c(Cl)c1)CCNC3
Temperature: 80 °C

Procedure:
tert-Butyl 4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 56A (210 mg, 0.34 mmol) was dissolved in 2-propanol, and 4 M gaseous hydrogen chloride in dioxane (0.17 mL, 0.67 mmol) was added. The mixture was heated to 80° C. for 3 h. The precipitate was collected by suction filtration and dissolved in diluted aqueous sodium hydroxide solution. Some methanol was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The title compound was crystallized from dichloromethane/diethyl ether to yield 116 mg (77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14](=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[C:15](Cl)=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14](=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[C:15]([NH2:25])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCn1cc2c(n1)c(Cl)nc1cc(OCc3ccccc3)ccc12
Solvent: CO
Product: CCn1cc2c(n1)c(N)nc1cc(OCc3ccccc3)ccc12
Temperature: 150 °C

Procedure:
A mixture of 7-benzyloxy-4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline (1.20 g, 3.55 mmol) and 7 N ammonia in methanol (25 mL) was heated in a pressure vessel at 150° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, purified via column chromatography on silica gel (eluting with 0-35% CMA/chloroform), concentrated under reduced pressure, and crystallized from acetonitrile to yield 0.93 g of 7-(benzyloxy)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a tan solid, mp 229-230° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:2]#[CH:3].[OH-].[Na+].[I:13]I.O>CO>[I:13][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: C#CCOc1cccnc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: IC#CCOc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
In 300 ml methanol was dissolved 39.0 g (0.27 mole) 3-(2-propynyloxy)pyridine. This solution was cooled to 0° C. and 54.0 g (1.35 moles) sodium hydroxide was added slowly while maintaining the temperature at 0°-5° C. Iodine (82.0 g, 0.32 mole) was added portionwise followed by the addition of 400 ml methanol. After stirring for 2 hours at room temperature, the reaction mixture was poured into cold water. The resulting precipitate was filtered and dried. This crude product was recrystallized from 350 ml methanol and 75 ml toluene to give 60.0 g (86% yield) 3-(3-iodo-2-propynyloxy)pyridine, mp 130° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[NH:59][CH2:58][CH2:57][CH2:56]2>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:59]2[C:60]3[C:55](=[CH:54][C:53]([F:52])=[CH:62][CH:61]=3)[CH2:56][CH2:57][CH2:58]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: Fc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
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: CN(C)C=O
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCCc2cc(F)ccc21
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
To a solution of 57 mg (0.2 mmol) 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76, intermediate a) in 1.5 mL N,N-dimethylformamide were added 91 mg (0.24 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.102 mL (0.6 mmol) N,N-diisopropyl-ethylamine. The solution was stirred 15 minutes at 45° C. followed by addition of 36 mg (0.22 mmol) 6-fluoro-1,2,3,4-tetrahydroquinoline (commercially available, CAS RN 59611-52-8). The reaction was stirred at 45° C. overnight and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 2.5 mg (3%) of the desired compound. MS (ESI): m/z=418.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](=[O:18])[C:13]2[S:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]([CH3:7])[C:5]#N.[OH-:19].[K+].C([OH:23])C>O>[CH3:1][C:2]1[C:11]([C:12](=[O:18])[C:13]2[S:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]([CH3:7])[C:5]([OH:23])=[O:19]
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1c(C(=O)c2cccs2)cccc1C(C)C#N
Agent: [K+]
Solvent: O
Product: Cc1c(C(=O)c2cccs2)cccc1C(C)C(=O)O

Procedure:
A mixture of 6 parts of 2-methyl-3-(2-thenoyl)hydratroponitrile, 2.7 parts of potassium hydroxide, 28 parts of ethanol and 3.5 parts of water is stirred and refluxed for 44 hours. The reaction mixture is evaporated. The residue is taken up in water and washed twice with 80 parts of ether. The aqueous phase is acidified with concentrated hydrochloric acid solution. The separated oily product is extracted with ether. Then the latter is dried and evaporated. The oily residue solidifies on triturating in petroleumether. The product is crystallized from acetonitrile at -20° C, yielding a first fraction of 2-methyl-3-(2-thenoyl)hydratropic acid; mp. 118.7° C. The mother-liquor is evaporated. The residue solidifies on triturating in petroleumether, yielding a second fraction of 2-methyl-3-(2-thenoyl)hydratropic acid; mp. 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C:20]([O:39][CH2:40][CH2:41][C@@H:42](O)[CH3:43])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:45]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[C@H:43]([CH3:45])[CH2:42][CH2:41][CH2:40][O:39][C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1Cl)c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
To N-(2,5-dichlorophenyl)-4-chlorobenzenesulfonamide (5.0 g, 15 mmol), (S) -4-trityloxy-butan-2-ol (7.7 g, 22 mmol), and triphenylphosphine (5.8 g, 22 mmol) in THF (200 mL) at 0° C. was added diethyl azodicarboxylate (3.8 g, 22 mmol). The reaction was allowed to warm to ambient temperature with stirring 18 h The reaction was then diluted with EtOAc and washed with H2O, 1N HCl, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (15% EtOAc/hexanes) of the concentrate afforded the title compound as a white solid (5.25 g, 55% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[C:13](Cl)([Cl:15])=[O:14]>C1COCC1>[C:13]([Cl:15])(=[O:14])[O:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)OCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of naphthalen-2-yl methanol (51.2 g, 324 mmol) dissolved in anhydrous THF (1 L) was treated with phosgene (205 mL, 20% solution in toluene, 388 mmol). The solution was stirred at ambient temperature for 45 minutes and then concentrated to afford the desired product as a solid, which was dried under vacuum and used directly in the next step.