Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH:6]([CH3:10])[C:7](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].O1CCOCC1.P(Cl)(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH:6]([C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:10]
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: NNC(N)=S
Solvent: O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 9.4 grams (0.040 mole) of 2-(3,4-dichlorophenoxy)propanoic acid, (3.6 grams, 0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane and heated to 90° C. The addition funnel was charged with phosphorous oxychloride (POCl3), (6.7 grams, 0.044 mole) which was slowly added (for 15 minutes) while maintaining the temperature within 85°-90° C. The resulting mixture was refluxed for approximately 100 minutes, and then topped with a water aspirator to remove volatiles (HCl, POCl3 and some dioxane). Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off and partially air dried, and was recrystallized from the minimum amount of H2O/ethanol mixture, filtered and then dried in a vacuum oven at 80° C. to 8.0 grams of fluffy white crystals of 5-[1-(3,4-dichlorophenoxy)ethyl]-2amino-1,3,4-thiadiazole. (Melting point 136°-138° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.C=O.[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1ccc2nnc([C@@H]3CCNC3)n2c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC[C@@H](c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 90c (225 mg, 1.09 mmol), formaldehyde (37% in water, 0.885 mL, 10.9 mmol) and AcOH (0.0625 mL, 1.09 mmol) in DCM (20 mL) and MeOH (1 mL) was added NaBH(OAc)3 (462 mg, 2.18 mmol) (CARE: gas evolution) and the pale yellow solution stirred at RT for 16 h. The solution was concentrated to 2 mL volume, then was applied to an SCX-2 cartridge and was washed with MeOH (25 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left the title compound as a pale brown viscous oil (228 mg, 95%). LCMS (Method 3): Rt 0.44 min, m/z 221 [MH+].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:12][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])([CH3:12])[CH3:2]
Reactant: CC(=O)c1cc(C#N)ccn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(C#N)ccn1
Temperature: -40 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 2-acetylisonicotinonitrile (67.1 g, 0.457 mol) in tetrahydrofuran (2400 mL) was added dropwise a solution of methylmagnesium bromide (3.0 M, 167.6 mL, 0.503 mol) in toluene/tetrahydrofuran mixture (3:1) at −40° C. over a period of 2.5 h. The reaction mixture was stirred at −40° C. for another 2 h. A saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture was warmed to room temperature and another 400 mL of a saturated aqueous solution of ammonium chloride was added. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL×2). The combined organics were dried over sodium carbonate and sodium sulfate and concentrated. The residue was purified via flash chromatography (ethyl acetate/petroleum ether 1:20, 0.3% triethylamine) to afford 2-(2-hydroxypropan-2-yl)isonicotinonitrile (33.0 g, 44.3%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(-c3cnc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a yellow solid (0.060 g, 23%). MS (ISP) 413.1 [(M+H)+], 415.2 [(M+2+H)+] and 417 [(M+4+H)+]; mp 237° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:11]([CH3:20])[CH:10]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][OH:28]>CC(C)=O>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][OH:28])(=[O:18])=[O:17])=[C:11]([CH3:20])[CH:10]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
K2CO3 (20.40 g, 147.6 mmol) and 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (19.05 g, 81.2 mmol) were added in succession to a suspension of piperidin-2-ylmethanol (8.50 g, 73.8 mmol) in acetone (350 ml). The reaction mixture was then stirred at 50° C. overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was employed in the next stage without further purification. The yield was 27.25 g (quantitative).
Reaction SMILES: [F:1][C:2]([F:38])([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=2[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=1)[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47]>CN1C(=O)CCC1>[CH2:47]([N:25]([C:22]1[CH:23]=[CH:24][C:19]([C:2]([F:38])([F:1])[C:3]([F:18])([F:17])[C:4]([F:15])([F:16])[C:5]([F:13])([F:14])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36])[CH:46]=[CH2:45]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCN(c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of N-[4-(perfluorohexyl)phenyl]-2,4-dinitrobenzenamine (3.6 g, 6.2 mmol), NMP (40 mL), potassium carbonate (3.0 g) and allyl bromide (0.65 mL) was stirred at 75° C. for 4 hr. The mixture was extracted in the normal fashion, and the product recrystallized to give N-allyl-N-[4-(perfluorohexyl)phenyl]-2,4-dinitrobenzenamine (2.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[CH3:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([S:41]([C:37]3[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=3)(=[O:43])=[O:42])[C:13]2=[O:26])=[CH:20][CH:19]=1)([CH3:24])[C:22]#[N:23]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(C)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added m-methylbenzene-1-sulfonyl chloride (83.5 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 25 mg (17%); 1H NMR (CDCl3, 300 MHz): δ 9.551 (s, 1H), 8.046-8.095 (d, 3H, J=8.4 Hz), 7.762-7.791 (d, 2H, J=8.7 Hz), 7.354-7.575 (m, 5H), 6.670 (s, 1H), 2.436 (s, 3H), 2.212 (s, 3H), 1.855 (s, 6H); MS: m/z 497 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1.[Na]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)C1CC1
Agent: [Na]
Product: CC(C)(Cc1c(C(=O)C2CC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using cyclopropanecarbonyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt·1 H2O: Calc. C 67.27; H 5.31; N 4.61 Found C 67.27; H 5.16; N. 4.58.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:11]([O-])=O.[Na+]>O>[Cl-:1].[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N+:4]#[N:11]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc(Cl)c1Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 25 g (0.15 mole) 2,3-dichloroaniline in 16 ml H2O, add 39 ml (0.46 mole) concentrated HCl. Stir the mixture at room temperature for about five minutes. Cool the mixture to -5° to 0° C. and add dropwise a solution of 11 g (0.16 mole) NaNO2 in 30 ml H2O. Stir the resulting solution at -5° to 0° C. for about 30 minutes, then filter the solution into an ice-cooled filter flask. Keep the filtrate containing the diazonium salt at about 0° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Br[CH2:43][CH2:44]Cl.P(=O)(O)(O)O.[K]>C(#N)C>[N:1]1([C@:2]23[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:35])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:44][CH2:43]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCBr
Agent: O=P(O)(O)O
Agent: [K]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C

Procedure:
To a sealable vial was added ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.1 g, 0.178 mmol), 1-bromo-2-chloroethane (0.148 mL, 1.780 mmol) and phosphoric acid, potassium salt (0.189 g, 0.890 mmol). The mixture was diluted with acetonitrile (1.5 mL), was flushed with nitrogen, then was sealed and heated to 120° C. After 17.5 h of heating, the mixture was cooled to rt and some of the solids were removed by filtration. The filtrate was concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate as the crude product which was used in the next step with no additional purification. LCMS: m/e 588.7 (M+H)+, 2.30 min (method 1).
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([O:45]C(=O)C)[CH:37]=2)[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)(Cl)Cl.C(Cl)Cl>[N:14]1[CH:15]=[CH:16][C:11]([NH:10][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])=[CH:37][C:38]=2[OH:45])=[CH:12][CH:13]=1
Reactant: Nc1ccncc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccncc3)c(O)c2)=C(C)C1=O
Yield: 7 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (43 mg, 0.257 mmol), 4-aminopyridine (24 mg, 0.257 mmol) and triethylamine (26 mg, 0.257 mmol) were added to a methylene chloride solution (5 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (64 mg, 0.171 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. Subsequently, an aqueous saturated sodium hydrogencarbonate solution (10 ml) was added to a methanol solution (4 ml) of the obtained residue and the resulting solution was stirred for 1 hour. The reaction solution was extracted with ethyl acetate, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1) to obtain the titled compound (5 mg, 0.012 mmol, 7.2%).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:16](N)=[NH:17].C([N:22](C(C)C)CC)(C)C>CC(N(C)C)=O>[F:11][C:8]1[C:9]([F:10])=[C:2]2[C:3]([C:4]([NH2:22])=[N:5][CH:16]=[N:17]2)=[CH:6][CH:7]=1
Reactant: N=CN
Reactant: N#Cc1ccc(F)c(F)c1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Nc1ncnc2c(F)c(F)ccc12
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
2,3,4-Trifluoro-benzonitrile (3.00 g, 19.1 mmol) is mixed with dimethylacetamide (30 mL). Formamidine acetate (1.99 g, 19.1 mmol) and diisopropylethyl amine (10 mL, 57.3 mmol) are added, and the resulting reaction mixture is slowly heated. Upon heating, the starting heterogeneous mixture slowly turns into a homogeneous solution. At 80° C., precipitates start to form. The reaction mixture proceeds at 80° C. for ˜30 minutes before it is cooled and filtered. The collected solid is further washed with DCM to afford 1.50 g of 7,8-Difluoro-quinazolin-4-ylamine (43% yield) as white solid. LC/MS found m/z=182 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[Mg].[CH3:39]I.[Cl-].[NH4+].[CH2:43]([O:45]CC)C>C(OCC)(=O)C.O1CCCC1>[OH:31][CH:30]([C:29]1[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:7]2[C:6]([CH:5]([O:45][CH3:43])[C:4]3[CH:3]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:11]([O:12][CH2:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:10]=[CH:9][N:8]=2)(=[O:24])=[O:25])=[CH:33][CH:32]=1)[CH3:39]
Reactant: COc1ccccc1Cc1c(NS(=O)(=O)c2ccc(C=O)cc2)ncnc1OCCOC1CCCCO1
Reactant: CCOCC
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(c1ccccc1)c1c(NS(=O)(=O)c2ccc(C(C)O)cc2)ncnc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
170 mg of rac-p-[[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl]oxy]ethoxy]-4-pyrimidinyl]sulfamoyl]benzaldehyde and, after 30 minutes, 1 ml of absolute tetrahydrofuran were added at room temperature to a Grignard solution prepared from 60 mg of magnesium and 0.15 ml of methyl iodide in diethyl ether. After stirring at room temperature for 3 hours, the reaction was interrupted by the addition of saturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried and evaporated under reduced pressure. The residue was chromatographed over 35 g of SiO2 with CH2Cl2 /ethyl acetate (8:2) and (1:1) and yielded 135 mg of p-[(RS)-1-hydroxyethyl]-N-[5-(methoxybenzyl)-6-[2-[[(RS)-tetrahydro-2H-pyran-2-yl]oxy]ethoxy]-4-pyrimidinyl]benzene-sulfonamide melting point >56° C. (sublimation).
Reaction SMILES: CO[C:3](=[O:25])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:26][C:27]([F:32])([F:31])C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCOCC>C(Cl)Cl>[C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[C:3](=[O:25])[C:27]([F:32])([F:31])[F:26])=[O:24])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CCCC1C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 2 %

Procedure:
4.0 g (10.6 mmol) of the title compound of Example 25 was dissolved in 50 ml of methylene chloride at room temperature under an atmosphere of nitrogen. 20 ml (260 mmol) trifluoroacetic acid (TFA) was added and the solution refluxed for 2 hours to hydrolyze the ester. Solvent and excess TFA were then removed under reduced pressure, the residue was redissolved in 22.5 ml (159 mmol) of trifluoroacetic anhydride (TFAA), and the solution ref luxed for 12 hours. The TFAA was evaporated under high vacuum at 80° C. to give an impure yellow gum. Flash chromatography on silica gel with 100% ether afforded 80 mg (2%) of the title compound as a yellow foam. TLC (Ether): Rf =0.50. 1H NMR (CDCl3) δ: 7.32-7.84(m,9H); 4.30-4.96(m,1H); 3.20-3.54 (M,2H); 1.68-2.48(m,4H). High Resolution Mass Spectrum: 376.1170±0.9 ppm (calculated for C20H17NO3F3). 2,4-DNP test: positive
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-:18].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[ClH:18].[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: [Cl-]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Veratrole (7 g, 0.05 mol) was added dropwise over 30 min to a stirred suspension of succinic anhydride (6 g, 0.6 mol) and Aluminium chloride (16 g, 0.12 mol) in 40 ml of nitrobenzene at 10° C. The temperature was then slowly raised to room temperature and was stirred at room temperature for 12 hours. The reaction mixture was then poured over ice cold water and then acidified with Con HCl. The solid product was filtered off and then redissolved in 1 N NaOH and extracted with ether. The ethereal layer was discarded and the aqueous layer was acidified with Con. HCl to obtain the required product. The pale yellow product was filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.[CH:22]1([C:25](=[O:32])[CH:26]=[C:27](SC)[S:28][CH3:29])[CH2:24][CH2:23]1>O1CCOCC1>[CH:22]1([C:25](=[O:32])/[CH:26]=[C:27](/[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]3[C:9](=[O:20])[N:10]([CH3:19])[C:11]4[C:16]([CH:17]=3)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=4)[CH:7]=2)\[S:28][CH3:29])[CH2:24][CH2:23]1
Reactant: CSC(=CC(=O)C1CC1)SC
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Solvent: C1COCCO1
Product: CS/C(=C\C(=O)C1CC1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Temperature: 150 °C

Procedure:
The mixture of 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (165 mg, 0.589 mmol) and 1-cyclopropyl-3,3-bis(methylthio)prop-2-en-1-one 30 (111 mg, 0.589 mmol) in 1,4-dioxane (2 mL) was heated in a sealed vial at 150° C. overnight. The solvent was removed to yield crude (Z)-3-(5-(3-cyclopropyl-1-(methylthio)-3-oxoprop-1-enylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 31 which was used without further purification. MS m/z 420.1 (M+1).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([N:33]([CH3:45])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]([CH3:44])[S:40](=[O:43])(=[O:42])[NH2:41])=[O:32])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO.C1COCC1>[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([N:33]([CH3:45])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]([CH3:44])[S:40](=[O:42])(=[O:43])[NH2:41])=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)N(C)CCOCCN(C)S(N)(=O)=O)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Reaction time: 5 h
Yield: 83 %

Procedure:
A solution of NaOH (1.00 g, 25 mmol) in water (5 mL) was added to a stirred solution of intermediate 7 (370 mg, 0.602 mmol) in MeOH (30 mL) and THF (10 mL). After 5 h, the solution was concentrated under vacuum. The pH was then adjusted to 5 with acetic acid (AcOH). Then, the reaction mixture was extracted with AcOEt, the organic layer dried over anhydrous Na2SO4, filtered and the filtrate evaporated to yield 300 mg (83%) of 3-cyclohexyl-1-methyl-2-(2-{2-[methyl(2-{2-[methyl(sulfamoyl)amino]ethoxy}ethyl)amino]-2-oxoethoxy}phenyl)-1H-indole-6-carboxylic acid 8 as a white powder: m/z=601 (M+H)+.