Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:6]=[CH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])CCC.C[CH2:15][O:16][C:17]([CH2:19][C:20]([NH2:22])=[O:21])=[O:18].C[O-].[Na+].Cl>CO.O>[O:21]=[C:20]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:22]1
Reactant: CCOC(=O)CC(N)=O
Reactant: CCCCOC=CC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 2.0 g (0.0102 mol) of 4-butoxy-1,1,1-trifluoro-3-buten-2-one (VIIIa) and 1.3 g (0.0102 mol) of ethyl malonate monoamide in 10 mL methyl alcohol was added 2.2 mL (0.0102 mol) of a 25% solution of sodium methoxide in methanol. The solution turned into a thick yellow suspension which was refluxed overnight. The suspension was cooled to room temperature, poured into water, acidified with one normal hydrochloric acid and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to afford 1.7 g (74%) of a yellow solid. m.p. 63°-64° C.; 1H NMR (CDCl3) δ4.0 (3H, s), 7.33 (1H, d, J=8 Hz), 8.4 (1H, d, J=8 Hz); IR (mineral oil) 3080, 1675 (br), 1605, 1450, 1375 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A stirring solution of 240 mg (1.03 mmol) of 3-Methyl-1 tert-butoxycarbonyl-pyrazolo[3,4-b]pyridine, prepared as in Part B, in 10 mL of CCl4 is heated to reflux, and then a mixture of 220 mg (1.23 mmol, 1.2 equiv) of N-bromosuccinimide and 25 mg (0.10 mmol, 0.1 equiv) of benzoyl peroxide is added all at once as a solid. The resulting solution is heated at reflux for 3.5 h, then cooled to RT. The reaction mixture is filtered through a pad of Celite to remove the precipitated succinimide, and the solvent is removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 3/1 as eluent afforded 170 mg of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) δ8.75 (dd, 1H, J=1.4, 4.6), 8.21 (dd, 1H, J=1.4, 8.0), 7.32 (dd, 1H, J=4.6, 8.0), 4.74 (s, 2H), 1.70 (s, 9H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:24]([O:26][CH2:27][CH2:28][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)(=[O:25])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCN1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1

Procedure:
20 grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril and 3 ml of ethyl 2-bromoacetate and 1.5 ml of triethylamine are mixed with 20 ml of dimethyl formamide at 50°-60° C. for 8 hours under stirring conditions. The reaction mixture is concentrated under reduced pressure and to the viscous residue thus obtained are added 30 ml of 2% sodium hydrogen-carbonate aqueous solution followed by extraction with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography and recrystallized from isopropanol to obtain 5-{3-[4-(2-acetyloxyethyl)piperazinyl]-propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 131°-132° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Cl.C(N(CC)CC)C.[N-:20]=[N+:21]=[N-:22].[Na+]>COCCOC>[NH:20]1[C:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[CH:6]3)=[N:2][N:22]=[N:21]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: c1cc2cc(-c3nnn[nH]3)ccc2[nH]1

Procedure:
A mixture of 5-cyano-1H-indole (88 g), triethylamine hydrochloride (225 g), and sodium azide (150 g) was heated in 1,2-dimethoxyethane (DME) at reflux temperature for 48 hours. The solvent was evaporated in vaciio and the residue was dissolved in ethyl acetate (500 mL) and water (500 mL). pH was adjusted to 10 by addition of concentrated aqueous NaOH solution. The aqueous phase was separated and pH was adjusted to 4 by addition of acetic acid. The precipitated crystalline title compound 1a was filtered off and subsequently dried in vacuo. Yield 82 g, mp 205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cncc(F)c4)c3)c2cc1OC
Yield: 62.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (159 mg, 0.45 mmol) described in Example 326A to afford 1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (107 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.28 (s, 9H), 3.99 (m, 6H), 6.43 (s, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.34 (d, J=4.5 Hz, 2H), 7.38-7.47 (m, 2H), 7.54 (s, 1H), 7.98 (d, J=9.9 Hz, 1H), 8.61-8.72 (m, 4H), 9.25 (s, 1H); LC-MS (ESI) m/z 574 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Reaction time: 18 h
Yield: 24.5 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (89 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (0.079 mL, 0.56 mmol) was added, followed by methanesulfonyl chloride (0.022 mL, 0.28 mmol). The mixture was stirred at it for 18 h and then at 50° C. overnight. The mixture was concentrated, diluted with MeOH, filtered and the filtrate purified by HPLC eluting with 20-95% gradient acetonitrile/water to afford 24 mg (25%) of the title compound. 1H-NMR (CD2Cl2-d2) 8.13-8.06 (m, 2 H), 7.81 (dt, 1H), 7.77-7.76 (m, 1 H), 7.43 (s, 1H), 7.42-7.33, (m, 5 H), 7.19 (dd, 1 H), 5.64 (s, 1 H), 4.61-4.53 (m, 1 H), 3.74-3.65 (m, 2 H), 3.54-3.44 (m, 1 H), 3.39-3.31 (m, 1 H), 2.89 (s, 1 H), 2.46-2.28 (m, 2 H); LC-MS [M+H]+=516.2, RT=2.88 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)=[CH:3][N:2]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(-c2ccnnc2)cc1
Temperature: 0 °C

Procedure:
Ethyl 2-(4-(pyridazin-4-yl)phenyl)acetate 37-3 (150 mg, 0.62 mmol) and NaOH (120 mg, 3 mmol) was mixed in dioxane (1.5 mL) and H2O (1.5 mL) and stirred at 80° C. for 1 hour. After cooled down to 0° C., the mixture was treated with 1 N HCl aqueous solution to pH 1, and taken to dryness by rotary evaporation. The crude product was extracted with ethyl acetate (100 mL×3). The combined organic phases were concentrated to give 2-(4-(pyridazin-4-yl)phenyl)acetic acid 37-4 as pale yellow solid. MS m/z 215.1 (M+1)
Reaction SMILES: CO[C:3]1(OC)[CH2:7][CH2:6][CH2:5]O1.[Cl-].ClC1C=C[NH+]=CC=1.[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[CH:22][S:21][C:20]=1[C:32]([O:34][CH3:35])=[O:33]>O1CCOCC1>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:19]([N:18]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:20]([C:32]([O:34][CH3:35])=[O:33])[S:21][CH:22]=1
Reactant: COC1(OC)CCCO1
Reactant: COC(=O)c1scc(-c2ccccc2OC)c1N
Agent: Clc1cc[nH+]cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1scc(-c2ccccc2OC)c1-n1cccc1

Procedure:
5.2 mmol of dimethoxytetrahydrofuran and 5.2 mmol of 4-chloropyridinium chloride in 100 ml of dioxane are stirred for 15 minutes at ambient temperature and then 5.2 mmol of the compound obtained in Step C are added. The reaction mixture is then heated at reflux of the solvent for 3 hours and subsequently filtered. After concentrating the filtrate under reduced pressure, the residue obtained is crystallised by trituration in ethyl ether, allowing the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.[NH2:15][CH2:16][C@@H:17]([OH:20])[CH2:18][OH:19]>C(O)(C)C>[C:9]([O:8][C:6]([C:5]1[CH:4]=[N:3][C:2]([NH:15][CH2:16][C@@H:17]([OH:20])[CH2:18][OH:19])=[CH:14][CH:13]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: NC[C@@H](O)CO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1ccc(NC[C@@H](O)CO)nc1
Temperature: 100 °C

Procedure:
A mixture of t-butyl 6-chloronicotinate (4.69 g, 0.0220 mol) and (R)-3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml) was heated at 100° C. overnight. Solvent was removed under vacuum, and the residue taken up in ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated to give nearly pure product as a yellow oil. Yield 5.90 g (99%). 1H NMR. MS: 269 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[C:22]([O:24]CC)=O)=[N:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.CCO.[CH3:35][NH2:36]>O>[CH3:35][NH:36][C:22](=[O:24])[C:21]1[CH:27]=[CH:28][CH:29]=[C:19]([C:16]2[N:14]3[CH:15]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:31])[F:30])=[CH:5][CH:6]=4)[CH:11]=[CH:12][C:13]3=[N:18][N:17]=2)[CH:20]=1
Reactant: CCOC(=O)c1cccc(-c2nnc3ccc(-c4ccc(OC(F)(F)F)cc4)cn23)c1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNC(=O)c1cccc(-c2nnc3ccc(-c4ccc(OC(F)(F)F)cc4)cn23)c1

Procedure:
Ethyl 3-(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate, prepared as described above was stirred in 40% CH3NH2 in H2O 2O (2.5 mL) and EtOH (1.5 mL) at 60° C. in a sealed tube overnight. The reaction mixture was concentrated and purified by HPLC followed by further purification with prep-TLC (5% MeOH/CH2Cl2) to afford N-methyl-3-(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzamide.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[NH:23]([CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1
Yield: 79 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and aniline, the title compound was synthesized in the same manner as in Example 297. Yield: 79%. Melting point: 151-152° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[CH3:14][CH:15]1[CH2:20][NH:19][CH2:18][CH:17]([CH3:21])[NH:16]1.C(NC(C)C)(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:19]1[CH2:18][CH:17]([CH3:21])[NH:16][CH:15]([CH3:14])[CH2:20]1
Reactant: CC1CNCC(C)N1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CC(C)NC(C)C1

Procedure:
To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added 2,6-dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to afford compound 5.
Reaction SMILES: O[CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:45]=[N+:46]=[N-:47].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[N:45]([CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)=[N+:46]=[N-:47]
Reactant: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3cc4c(cc32)OCO4)cc1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 3.06 g (9.0 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (starting compound III.) and 2.58 g (9.9 mmol) of triphenylphosphine in 100 ml of dry tetrahydrofuran is mixed with 13.5 ml of a 1.2N hydrazoic acid solution in toluene, then a solution of 1.74 ml (9.9 mmol) of azodicarboxylic acid-diethyl ester is added, and the mixture is stirred for another 2 hours. The precipitated product is suctioned off and washed with tetrahydrofuran and n-hexane. 2.23 g (68%) of the title compound with a melting point of 198-200° C. is obtained.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:12])[C:10]#[CH:11]>C(#N)C>[C:1]([NH:3][C:4](=[N:12][CH2:9][C:10]#[CH:11])[S:5][CH3:6])#[N:2]
Reactant: C#CCN
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: C#CCN=C(NC#N)SC
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (16.0 g; 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, then at ambient temperature for 12 hours. Workup gave 13.58 g (85%) of N-cyano-N'-(2-propyn-1-yl)-S-methylisothiourea; mp 160°-164°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=C(C#N)[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([OH:15])(=[O:14])[CH3:13]>O.OS(O)(=O)=O>[F:8][C:7]1[C:2]([F:1])=[C:3]([OH:11])[CH:4]=[CH:5][C:13]=1[C:12]([OH:15])=[O:14]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(O)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(O)c(F)c1F
Yield: 71 %

Procedure:
A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), H2SO4 (8 mL), and acetic acid (8 mL) was refluxed for 48 hours. The solvents were removed by rotary evaporation to give a slurry which was poured onto ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 71%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[C:14]([F:17])([F:16])[F:15]
Reactant: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1oc(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
359 mg (1.137 mmol, 76% purity) of the compound from Example 23A are initially charged in 0.63 ml (8.64 mmol) of thionyl chloride. The reaction mixture is stirred at RT for 48 h. After concentration on a rotary evaporator, the residue is taken up in 10 ml of ethyl acetate and washed once with 5 ml of sat. aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 400:1→60:1). This gives a light-brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[CH:18]=[C:17]([CH2:24][OH:25])[CH:16]=1>ClCCl>[Br:1][C:18]1[C:19]2[CH:20]=[CH:21][O:22][C:23]=2[C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][CH3:9])=[CH:16][C:17]=1[CH2:24][OH:25]
Reactant: COCCCOc1cc(CO)cc2ccoc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCCCOc1cc(CO)c(Br)c2ccoc12
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
N-Bromosuccinimide (978 mg) was added to a solution of [7-(3-methoxypropoxy)-1-benzofuran-5-yl]methanol (1.18 g) in dichloromethane (30 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1) to give [4-bromo-7-(3-methoxypropoxy)-1-benzofuran-5-yl]methanol (1.46 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][CH:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution containing 2-bromo-5-fluorophenol (50 g, 0.26 mol) in 500 mL acetone was added potassium carbonate (54.2 g, 0.39 mmol) and benzyl bromide (34.3 mL, 0.288 mol). The reaction was heated at reflux under an argon atmosphere for 2 h and then allowed to cool to 25° C. The acetone was removed under reduced pressure and the residue was taken up in ether (400 mL). The organic layer was washed with water (5×100 mL) and brine (1×100 mL) and then dried (MgSO4). The solution was then concentrated under reduced pressure and subjected to flash chromatography using hexane as the eluent. In this manner, 2-benzyloxy-4-fluorobenzene was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 5.14 (s, 2 H), 6.57-6.63 (m, 1 H), 6.69 (dd, J=2.7, 10.2 Hz, 1 H), 7.32-7.52 (m, 6 H).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].C(N(CC)C(C)C)(C)C.Cl[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:5][C:2](=[CH2:1])[CH2:3][NH:4][S:18]([CH:17]=[CH2:16])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)CCCl
Reactant: C=C(C)CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)NCC(=C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a stirred solution of 2-methylprop-2-en-1-amine (0.500 g, 7.0 mmol), N,N-diisopropylethylamine (3.486 mL, 21.1 mmol) and N,N-4-dimethylaminopyridine (0.043 g, 0.4 mmol) in methylene chloride (20 mL) at 0° C. was slowly added 2-chloroethanesulfonyl chloride (0.734 mL, 7.0 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue purified by silica gel chromatography (0-80% ethyl acetate/hexanes) to afford the product as a colorless oil (0.59 g, 52%). 1H NMR (300 MHz, CDCl3) δ 6.54 (dd, 1H, J=16.5, 9.6 Hz), 6.27 (d, 1H, J=16.5 Hz), 5.96 (d, 1H, J=9.6 Hz), 4.97 (s, 1H), 4.93 (s, 1H), 4.37 (br s, 1H), 3.60 (d, 2H, J=6.3 Hz), 1.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-dimethylphenyl)acetic acid (2.32 g in 25 mL dry methylene chloride) at 0° C. was added 0.055 mL N,N-dimethylformamide followed by the dropwise addition of 1.3 mL of oxalyl chloride. After 15 minutes the mixture was warmed to room temperature and stirred for an additional 2 hours. Removal of the solvents in vacuo provided the title compound which was used without purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)=[CH:44][CH:43]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3ccnc3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-imidazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.