Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1F

Procedure:
A suspension of 2,4-difluorobenzoic acid (3.6 g, 22.8 mmol) in dichloromethane (40 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (2.4 mL, 27.5 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes, and then the solution was evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2.[C:30]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:42].Cl>>[ClH:42].[ClH:42].[CH3:30][N:27]1[CH2:28][CH2:29][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[CH:13][C:12]4=[O:25])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:26]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CNCC2
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc3n2C)C1
Yield: 98 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one (45 mg, 0.116 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (54 mg, 98%) as a white solid: mp 260-265° C.; 1H NMR (500 MHz, CD3OD) δ 8.87 (d, J=5.7 Hz, 1H), 8.58 (overlapping dd, J=8.2 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 8.00 (overlapping dd, J=6.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.07 (dd, J=8.3, 1.7 Hz, 1H), 6.44 (dd, J=7.5, 2.6 Hz, 1H), 6.20 (d, J=2.0 Hz, 1H), 5.56 (s, 2H), 4.76 (d, J=14.2 Hz, 1H), 4.40 (d, J=14.2 Hz, 1H), 3.91 (m, 1H), 3.74 (s, 3H), 3.61 (m, 1H), 3.29-3.17 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 401 [M+H]+; HPLC (Method B)>99% (AUC), tR=9.2 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])C=O)=[CH:4][C:3]=1[F:12].C1(C)C=CC=CC=1.[CH:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])OCC.C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:20]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:4][C:3]=1[F:12]
Reactant: O=CC(=O)c1ccc(Br)c(F)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Temperature: 110 °C
Reaction time: 6 h
Yield: 92.1 %

Procedure:
A 22 L flask was charged with the hydrate of (4-bromo-3-fluorophenyl)-2-oxoacetaldehyde (5, 1020 g, 4.41 mol), toluene (7.5 L), triethyl orthoformate (1633 g, 1.8 L, 11.04 mol, 2.5 equiv), para-toluene sulfonic acid (33.5 g, 0.176 mol, 0.4 equiv) at room temperature, and the resulting reaction mixture was heated to 110° C. and stirred at 110° C. for 6 h. When HPLC showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being poured into a 50 L separation funnel along with ethyl acetate (7.5 L) and the saturated aqueous sodium bicarbonate solution (NaHCO3, 3 L). The mixture was stirred and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were washed with brine (4 L), dried with sodium sulfate (Na2SO4), and concentrated under the reduced pressure to afford crude 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (6, 1240 g, 1345.7 g theoretical, 92.1% yield) which was used in the subsequent reaction without further purification. For 6: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94-7.94 (m, 2H), 7.78 (dd, 1H, J=8.51, 2.08 Hz), 5.40 (s, 1H), 3.77-3.60 (m, 4H), 1.16-1.14 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)[CH3:3].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[C:21]=1[CH:28]=[O:29]>CN(C)C=O>[CH:2]([N:4]1[C:8]([C:9]2[C:14]([CH2:15][O:16][C:20]3[C:21]([CH:28]=[O:29])=[C:22]([NH:26][CH3:27])[N:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)([CH3:1])[CH3:3]
Reactant: CC(C)n1nccc1-c1ncccc1CO
Reactant: CNc1nccc(Cl)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nccc(OCc2cccnc2-c2ccnn2C(C)C)c1C=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Steps 3 & 4. Into a 100-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (1.15 g, 5.29 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 mg, 13.25 mmol, 2.50 equiv, 60%) at 0° C. The mixture was stirred for 15 min at 0° C. To this was added 4-chloro-2-(methylamino)pyridine-3-carbaldehyde (900 mg, 5.28 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um, 19*100 mm, mobile phase, water with 0.1% TFA and MeCN (3.0% MeCN up to 20.0% in 5 min, up to 95.0% in 2 min, down to 3.0% in 1 min); Detector, waters 2489 254&220 nm. This resulted in 107.1 mg (6%) of 2-(methylamino)-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid. 1HNMR (400 MHz, DMSO, ppm): 8.72 (m, 1H), 8.17 (s, 1H), 7.91 (m, 1H), 7.52 (m, 3H), 6.56 (s, 1H), 6.26 (d, J=4.2 Hz, 1H), 6.15 (d, J=3.3 Hz, 1H), 5.43 (m, 1H), 5.12 (m, 1H), 4.60 (m, 1H), 2.87 (d, J=3.3 Hz, 1H), 1.46 (d, J=5.1 Hz, 1H), 1.35 (d, J=5.1 Hz, 1H); (ES, m/z): 352.1 [M+1]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].O>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc12
Yield: 74.7 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 200 mg, 0.95 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (510 mg, 2.85 mmol) in THF (4 mL) was stirred at rt for 2 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.47 (s, 1H), 8.83-8.80 (d, J=8.4 Hz, 1H), 8.72 (s, 1H), 8.42-8.39 (d, J=7.8 Hz, 1H), 8.31-8.25 (m, 2H), 7.86-7.81 (t, J=7.8 Hz, 1H), 7.64-7.58 (t, J=9.6 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:21])/[CH2:8][CH2:9][C:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12](=[O:19])[C:11]=1[CH3:20])(=[O:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:21])/[CH2:8][CH2:9][C:10]1[C:11]([CH3:20])=[C:12]([OH:19])[C:13]([CH3:18])=[C:14]([CH3:17])[C:15]=1[OH:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C=C(\C)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC/C=C(\C)CCc1c(C)c(O)c(C)c(C)c1O
Yield: 89 %

Procedure:
A solution of 3.27 g (11.3 mmol) of (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl acetate in 60 ml of THF was treated dropwise with 40 ml of a freshly Prepared 0.5M sodium dithionite solution. After completion of the addition the mixture was diluted with water and extracted with chloroform. The combined extracts were washed with water and freed from solvent. The solid residue was washed with hexane and dried under oil pump vacuum, yielding 2.94 g of (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate as a colourless powder; m.p. 94.5°-96° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[C:23]2=[O:30])=[CH:18][C:17]=1[F:31].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>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([F:31])[CH:18]=2)[C:23]1=[O:30])=[O:28]
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(Cl)c(F)c2)C1=O
Yield: 41.8 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(4-chloro-3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.115 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (42%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chloro-3-fluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.[H-].[Na+].I[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[CH:24]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h

Procedure:
2-chloro-6-(4-methoxybenzylamino)purine was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.N1C=CC=CC=1.[Cl:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:26]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)C(Cl)c1ccccc1

Procedure:
Synthesized according to general procedure 1: N′-(2-thiazolyl)sulfanilamide (5.60 g, 22 mmol), pyridine (3.6 mL, 44 mmol), 2-chloro-2-phenyl acetylchloride (3.8 mL, 26.4 mmol, 1.2 equiv) in DCM (400 mL). Yield: 6.73 g (75%) of a white solid. 1H-NMR (DMSO-d6) δ 10.85 (s, 1H), 7.78-7.72 (m, 4H), 7.60-7.57 (m, 2H), 7.45-7.37 (m, 3H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 5.77 (s, 1H). LC/MS (10-99%) M/Z: M+1 obs=408.1; tR=2.61 min.
Reaction SMILES: Cl.C[O:3][C:4](=[O:17])[CH2:5][C@@H:6]([NH2:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:16][C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:5][C:4]([OH:3])=[O:17])=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:30])=[O:31])[CH:20]=1
Reactant: COC(=O)C[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: O=C(O)C[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-4-(3,4-dichloro-phenyl)-butyric acid was treated as in EXAMPLE 2, Part A, to produce (S)-3-amino-4-(3,4-dichloro-phenyl)-butyric acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E. HPLC: RT=9.78 min. MS (ESI−): mass calcd. for C25H19Cl3N4O5S, 592.01; m/z found; 593/595 [M−H]−. 1H NMR (500 MHz, CD3OD): 8.97 (d, J=1.8, 1H), 8.93 (d, J=1.8, 1H), 8.55 (dd, J=7.4, 1.3, 1H), 8.33 (dd, J=8.5, 1.3, 1H), 7.97-7.94 (m, 1H), 7.69 (d, J=2.0, 1H), 7.42 (d, J=8.2, 1H), 7.38-7.36 (m, 2H), 7.16 (dd, J=8.2, 2.0, 1H), 6.97 (dd, J=8.6, 2.0, 1H), 4.56-4.50 (m, 1H), 2.90 (dd, J=13.7, 6.1, 1H), 2.81 (dd, J=13.7, 7.7, 1H), 2.54 (dd, J=15.9, 6.2, 1H), 2,45 (dd, J=15.9, 7.4, 1H).
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)(C)(C)C>C(Cl)Cl>[Cl:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 136.3 %

Procedure:
A 4 N solution of HCl in dioxane (11.7 mL, 46.9 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (Example 117) (0.50 g, 1.56 mmol) in CH2Cl2 (6.7 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 6.5 h. Additional 4 N HCl solution (1.1 mL, 4.6 mmol, 3.0 equiv) is added. The reaction mixture is allowed to stir for 0.5 h and concentrated in vacuo to afford 0.467 g of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. An 8 M solution of methylamine in EtOH (5.1 mL, 40.0 mmol, 30 equiv) Is added to a solution of crude 4-(6-chloro-pyrimidin-4-ylmethyl)phenylamine (0.300 g, 1.37 mmol) in EtOH (2.7 mL), under an argon atmosphere. The mixture Is heated to 50° C. (oil bath temperature) for 5 h, allowed to cool to rt and concentrated in vacuo. The residue is purified by silica gel (48 g) column chromatography (CH2Cl2/MeOH, 85/15) to afford the title compound as a light yellow oil: ES-MS: 215.0 [M+H]+; single peak at tR=3.03 min (System 2); Rf=0.49 (CH2Cl2/MeOH, 85/15).
Reaction SMILES: [C:1]1([CH:7]2[S:11]C(=N)N[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Ba+2].[OH-]>C(O)C>[SH:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:13])=[O:14]
Reactant: [OH-]
Reactant: N=C1NC(=O)C(c2ccccc2)S1
Agent: [Ba+2]
Solvent: CCO
Product: O=C(O)C(S)c1ccccc1
Yield: 70 %

Procedure:
Hydrolysis of 142 g of 5-phenyl-2-imino-4-thiazolidinone with barium hydroxide in 20% aqueous ethanol gave 55 g of α-mercaptophenylacetic acid (70% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[O:29]1[CH2:32][CH:31]([NH2:33])[CH2:30]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:33][CH:31]2[CH2:32][O:29][CH2:30]2)=[O:26])[CH:4]=[N:3]1
Reactant: NC1COC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)NC2COC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), oxetan-3-amine hydrochloride (60.5 mg, 552 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 20 hours at reflux under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried. The residue (94 mg white solid) is triturated with ethyl acetate, filtered and the filtrate is evaporated affording 1-methyl-N4-(oxetan-3-yl)-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (44 mg, 38.2%) as a white solid. mp.: >250° C. MS: m/z=418.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1)(=[O:26])=[O:25]
Reactant: Cc1ccnc(N2CCC(CO)CC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCC(COS(C)(=O)=O)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-(4-Methylpyridin-2-yl)piperidin-4-yl)methanol (0.970 mmol, 0.2 g) and triethylamine (2.91 mmol, 0.404 mL, 0.294 g) were stirred in DCM at 0° C. Methanesulfonyl chloride (1.454 mmol, 0.113 mL, 0.167 g) was added dropwise and the reaction allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was washed with water, dried over Na2SO4 and concentrated in vacuo to afford (1-(4-methylpyridin-2-yl)piperidin-4-yl)methyl methanesulfonate. (0.234 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:19][C:20]([CH3:24])([CH3:23])[CH:21]=O)[CH2:15][CH2:16][CH:17]=[CH2:18].C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:21][C:20]([S:19][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:24])[CH3:23]
Reactant: C=CCCCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.1 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.155 g, 7/9×10-4 mol) and 0.30 g (1.74×10-3 mol, 220 M%) of 2-(4-pentenylthio)-2-methylpropanal were dissolved in 40 ml methanol. Acetic acid (0.09 ml, 1.59×10-3 mol, 200 M%) was added followed by 0.155 g (2.3×10-3 mol, 300 M%) sodium cyanoborohydride. The reaction was stirred at room temperature under nitrogen for 17 hr, then 20 ml 0.5 M HCl was added and the mixture was extracted with 2×40 ml diethyl ether. The ether layer was washed with 30 ml saturated NaCl solution and dried (Na2SO4), and the solvent was removed on the rotary evaporator. The product was purified by radial chromatography on a 2 mm silica plate eluting with 50 ml 100% hexane and 100 ml 90% hexane/ether to give 0.27 g (97% yield) of 2-(2-mercapto-2-methylpropylamino)-1-[2-(4-pentenylthio)-2-methylpropylamino]-benzene as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br.Br>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(=O)CBr)cc1
Temperature: 45 °C

Procedure:
2.0 g (12.2 mmole) of 4-acetyl benzoic acid was added to 90 ml of acetic acid in a 500 ml erlenmeyer flask and heated at 45° C. until dissolved. Maintaining the temperature at 45° C., 1.95 g (12.2 mmole, 0.61 ml) of bromine dissolved in ~2 ml acetic acid was added slowly over 1 hour with vigorous stirring. The reaction required an induction period of several minutes before proceeding, which became evident by the loss of the red bromine color and the evolution of HBr. The product, BABA (Modifying Reagent II), was precipitated on ice, collected by filtration and recrystallized 3 times from hot (75° C.) ethanol.
Reaction SMILES: [S:1]1[C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:4][N:3]=[CH:2]1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:7])[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(C(=O)c2cncs2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(=O)c4cncs4)c(Cl)c3)c2cc1OC
Yield: 31 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-2-chlorophenyl 5-thiazolyl ketone was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(5-thiazolylcarbonyl)anilino]-6,7-dimethoxyquinazoline hydrochloride salt in 31% yield, m.p. 254°-257° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][C:6]([CH3:12])=[C:5]2[CH2:13][C:14]([O:16]C)=[O:15].[CH3:18][S:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])/[C:7](=[CH:26]\[C:25]1[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:29][CH:28]=1)/[C:6]([CH3:12])=[C:5]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CC1=C(C)Cc2cc(F)c(F)cc21
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)c(F)cc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
Methyl 5,6-difluoro-2-methylindene-3-acetate (1.19 g, 5.0 mmol) from Example 2, Part E and of p-methylsulfonylbenzaldehyde (0.76 g, 5.0 mmol) in dry pyridine (10 ml) are treated under nitrogen with Triton B (5.0 g, 5.1 mmol). The deeply colored solution is kept overnight. Water (2 ml) is added, the solution is stirred for 15 minutes and is poured into excess water. The mixture is extracted with ether (2×50 ml). The aqueous phase is added to 10% HCl-ice. The solution of the precipitate is extracted into methylene chloride and is dried (MgSO4). The solvent is evaporated to leave an orange solid which is recrystallized from benzene to give (Z)-5,6-difluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-indene-3-acetic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:26][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of 2-(trimethylsilyl)ethoxymethyl chloride (25.9 g, 0.155 mol) in CH2Cl2 (50 mL) was added dropwise to a solution of 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol from Step 1 (38.6 g, 0.120 mol) in the same solvent (500 mL) at 0° C. After completion of the addition, the mixture was allowed to warm to room temperature, and stirred for 3 h before it was diluted with CHCl3 (500 mL). The resulting solution was washed successively with 1N HCl (2×), saturated aqueous NaHCO3, water and brine, dried (Na2SO4) and concentrated. The residue was distilled under reduced pressure (bp 128° C./0.9 mmHg) to afford the title compound as a colorless liquid (50.0 g, 92%).