Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C2=CCCC2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 81.9 %

Procedure:
A mixture of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.6 mmol), tert-butyl 4-bromobenzoate (512 mg, 2 mmol), sodium carbonate (636 mg, 6 mmol) and tetra(triphenylphosphine) palladium (115 mg, 0.1 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred for 15 hours at 90° C. under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give tert-butyl 4-cyclopentenylbenzoate (400 mg, 82%) as a yellow oil. LRMS (M+H+) m/z: calcd 244.15. found 244. 1H NMR (300 MHz, CD3OD): δ 7.94-7.91 (m, 2H), 7.58-7.54 (m, 2H), 6.43-6.42 (m, 1H), 2.78-2.76 (m, 2H), 2.61-2.59 (m, 2H), 2.11-2.08 (m, 2H), 1.64 (s, 9H).
Reaction SMILES: O.[CH2:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:3][CH3:4].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH2:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccccc1O
Solvent: CCOCC
Solvent: O
Product: CCCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 288 h

Procedure:
To a stirred mixture of 100 ml of water, 100 ml of ether and 10.0 g of 2-n-propylphenol was added dropwise 11.0 ml of 61% nitric acid and the reaction was carried out with stirring at room temperature for 12 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)]to give 3.76 g of 6-n-propyl-2-nitrophenol.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:27][C:24]=1[CH:25]=O.C(OC(N1CCC[C@H](NCC2C=C(C(C(F)(F)F)C(F)(F)F)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([CH2:33][C:34]([F:35])([F:36])[F:37])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1cc(OC)c(CC(F)(F)F)cc1C=O
Agent: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1cc(OC)c(CC(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 85 in the same manner of Compound 13.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[C:14]([S:17]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:15]=[CH:16][C:6]=1[O:5][CH2:4][C:1]([NH2:2])=[O:3])(=[O:11])[NH2:12]
Reactant: COc1ccc(N)cc1
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(N)=O)c(OCC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Solid 2-[2-(carbamoylmethoxy)-5-(chlorosulfonyl)phenoxy acetamide (Intermediate A85, 161.25 g, 0.5 mol) was added to a solution of p-anisidine (49.2 g, 0.4 mol) in pyridine (3.5 L) and stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduce pressure. The residue was treated with 0.75 M hydrochloric acid (3 L) and the resulting solid was collected. The solid was washed with water (3×1 L), methanol (750 mL) and dried to give 99 g (60%) of the title compound, sulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12](O)=[O:13])[C:10]=2[CH:11]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O.COCCOC>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cnc2cccc(C(=O)O)c2c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: Cc1cnc2cccc(CO)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
35.0 g (187 mmol) of the compound from example 21A are introduced into 440 ml of 1,2-dimethoxyethane, 32.3 ml (233 mmol) of triethylamine are added, and the mixture is stirred at room temperature for 30 min Then 22.3 ml (233 mmol) of ethyl chloroformate are added dropwise at 15° C., and the mixture is stirred at room temperature for 15 min. The precipitated solid is filtered off and washed with 1,2-dimethoxyethane. The filtrate is then concentrated, and the residue is taken up in 440 ml of ethanol. 13.1 g (345 mmol) of sodium borohydride are added dropwise as a solution in 210 ml of water to the solution obtained in this way. After a reaction time of 16 h at room temperature, the precipitated solid is filtered off with suction and washed with ethanol, and the filtrate is concentrated in a rotary evaporator. The resulting residue is taken up in 800 ml of water and 600 ml of dichloromethane/methanol (8:2). The aqueous phase is again extracted with 600 ml of dichloromethane/methanol (8:2), and the combined organic phases are washed with saturated sodium chloride solution. Concentration and drying result in 23.0 g (71% of theory) of the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][C@@H:14]1[CH2:31][C:30]2[CH:29]=[C:28]([OH:32])[CH:27]=[CH:26][C:25]=2[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C@@H:19]([OH:33])[CH2:18][CH2:17]1)[CH2:2][CH2:3][CH3:4]>[Pd].C(OCC)(=O)C>[CH2:1]([NH:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[CH2:31][C:30]2[CH:29]=[C:28]([OH:32])[CH:27]=[CH:26][C:25]=2[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C@@H:19]([OH:33])[CH2:18][CH2:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCCC=CCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCNC(=O)CCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 1 h

Procedure:
5% Palladium-on-charcoal catalyst (0.025 g.) was added to a solution of N-n-butyl-8-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)oct-5-enamide (Example 3; 0.05 g.) in ethyl acetate (2.5 ml.) and the mixture was stirred at laboratory temperature under an atmosphere of hydrogen for 1 hour and then filtered. The filtrate was evaporated to dryness and there was thus obtained as oily residue N-n-butyl-8-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)octanamide, the structure of which was confirmed by spectroscopic means.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: O=S1(=O)COc2cc(F)ccc2N1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)COc2cc(F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.3 %

Procedure:
A mixture of the title compound of Step D (0.5 g, 2.46 mmol), K2CO3 (1.02 g, 7.38 mmol), benzyl bromide (0.463 g, 2.71 mmol) and TBAB (79 mg) in DMF (5 mL) was stirred at room temperature for 48 h. After the reaction was complete, the reaction mixture was poured into an H2O/ethyl acetate mixture (10/100 mL). The organic phase was separated, dried and concentrated to give the title compound of Step E as a brown solid (0.76 g). 1H NMR (CDCl3, 300 MHz): δ 7.32 (m,6H, aromatic) 6.72 (d,1H, 11 Hz), 6.34 (d,1H, 8 Hz), 4.82 (s,2H), 4.69 (s,2H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([CH2:35][NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])=[CH:44][CH:43]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 500 mg (1.33 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 10 ml methylenechloride were added 368 mg (1.46 mmol) 4-(tert-butoxycarbonylamino-methyl)-benzoic acid, 16.3 mg (0.133 mmol) DMAP und 511 mg (2.66 mmol) N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and the reaction mixture was stirred at 0° C. After 1 hour, 0.5 N HCl was added and the aqueous layer was extracted with methylenechloride. The combined organic layers were washed with 0.5N HCl solution and brine, dried over NaSO4, filtered and the solvent was removed under reduced pressure to give the crude product. Crystallization from diethylether yielded 280 mg (0.460 mmol, 35%) 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as colorless crystalls.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[C:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:24]=2)=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=O)C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+]>O1CCOCC1>[NH2:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[C:25]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[N:24]=2)=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(-c2nc(C(=O)c3ccc(NC(=O)c4ccccc4)c(C(=O)O)c3)n3ccccc23)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(=O)c3ccc(N)c(C(=O)O)c3)n3ccccc23)cc1

Procedure:
1.2 g of sodium hydroxide pellets are added to 0.259 g (0.5 mmol) of 2-benzoylamino-5-{[1-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]carbonyl}benzoic acid obtained in example 155 in solution in 25 ml of dioxane. The mixture is heated at reflux for 48 hours. The reaction medium is allowed to return to ambient temperature. The medium is taken up in dioxane and then acidified with potassium hydrogensulfate. The precipitate formed is filtered off, then rinsed with water and dried. 0.162 g of a yellow solid is collected, which solid is salified in the sodium salt.1.15H2O form. Melting point: 296° C.; 1H NMR (d6-DMSO): 3.85 (3H, s), 6.63 (1H, d), 7.09-7.17 (3H, m), 7.28-7.35 (1H, m), 7.96 (2H, d), 8.17 (1H, d), 8.34 (1H, d), 9.04 (1H, s), 9.69 (1H, d)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[S:44](Cl)(=[O:46])=[O:45]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)(=[O:46])=[O:45])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccccn2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 100 mg 5isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with thiophene-2-sulfonylchloride to give 85 mg 5-isopropyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.78 min, [M+1]+=683.61, [M−1]−=681.70.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].C(N(CC)CC)C.S(O)(O)(=O)=O.[NH2:30][C:31]1[N:40]=[C:39]([NH2:41])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=2)[N:32]=1>O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:42]([C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([NH2:30])[N:40]=[C:39]3[NH2:41])(=[O:43])=[O:44])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: Nc1nc(N)c2cc(S(=O)(=O)Cl)ccc2n1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4nc(N)nc(N)c4c3)C2=O)c1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.50 g, 2 mmol) in 8 mL of H2O is added triethyl amine (0.7 g, 7 mmol). After stirring for 10 minutes, 2,4-diamino-quinazoline-6-sulfonyl chloride sulfate salt (0.71 g, 2 mmol) is added. The solution is refluxed for 1 hour. After this time, the solution is cooled to ambient temperatures. The solution is filtered. The collected solid is dried under vacuum to give the title compound (0.22 g, 0.5 mmol) as a white solid.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:34][CH2:33][CH2:32][NH:31][C:30]2=[O:35])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:17]1([CH2:16][N:31]2[CH2:32][CH2:33][CH2:34][N:29]([C:21]3[S:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]([CH3:18])[N:20]=3)[C:30]2=[O:35])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1sc(N2CCCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCCN(CC3CC3)C2=O)nc1C

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with (bromomethyl)cyclopropane to react with ethyl 4-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 324.2 (M+1).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[O:9]=[C:10]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=[C:12]([C:19]([F:22])([F:21])[F:20])[NH:11]1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH:6]=[N:18][C:16]([C:15]1[C:10](=[O:9])[NH:11][C:12]([C:19]([F:20])([F:22])[F:21])=[CH:13][CH:14]=1)=[O:17])[CH3:5]
Reactant: NC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1ccc(C(F)(F)F)[nH]c1=O

Procedure:
0.87 g (7.28 mmol) of N,N-dimethylformamide dimethyl acetal was added to 1.00 g (4.85 mmol) of 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide in 5 ml of toluene, and the mixture was heated under reflux for 4 h. After cooling, the resulting precipitate was filtered off with suction and dried: 0.5 g (39% of theory).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]2[C:8]3[CH:15]=[CH:14][N:13](COCC[Si](C)(C)C)[C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:5][N:6]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[S:3][C:4]([C:7]2[C:8]3[CH:15]=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:5][N:6]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(Br)s3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ncc(-c2ncnc3[nH]ccc23)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
A solution of 4-(2-bromo-1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 7 hours. The mixture was then concentrated, re-dissolved in methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed with a small amount of DCM to afford desired product (182 mg, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl[C:17]1[CH:18]=[C:19]([CH3:30])[C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>C(O)C>[CH3:30][C:19]1[C:20]2[N:21]([C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][N:25]=2)[N:22]=[C:17]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH:18]=1
Reactant: Cc1cc(Cl)nn2c(C(F)(F)F)nnc12
Reactant: N#Cc1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: Cc1cc(N2CCN(Cc3ccc(C#N)cc3)CC2)nn2c(C(F)(F)F)nnc12
Temperature: 70 °C
Yield: 64.8 %

Procedure:
A mixture of 1-(4-cyanobenzyl)-piperazine (0.158 g, 0.79 mmol) and 6-chloro-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine 0.062 g, 0.26 mmol) in ethanol (5 mL) was heated to 70° C. for 20 hours. The reaction mixture was allowed to cool and then concentrated to give an involatile residue that was purified by flash chromatography on silica-gel using an increasing gradient of ethyl acetate in dichloromethane to give 4-((4-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)benzonitrile (0.0676 g, 64.3%) as a white solid; 1H NMR spectrum (CDCl3) δ 2.47-2.55 (4H, m), 2.61 (3H, d), 3.50-3.60 (6H, m), 6.72-6.76 (1H, m), 7.42 (2H, d), 7.57 (2H, d); m/z 402.69 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:15]([O:17][C:18](Cl)=[O:19])[CH3:16].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:16][CH2:15][O:17][C:18]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1)=[O:19]
Reactant: CCOC(=O)Cl
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (3.45 g 0.015 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (25 ml) was added ethylchloroformate (1.9 ml). The reaction mixture was stirred at 25° C. for 2 hours, poured into ice and excess hydrochloric acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and chromatographed after evaporation of the solvent on silica (150 g, 70-230 mesh) eluting with ethyl acetate-hexane 1:1 (v/v) to obtain 1.3 g of ethyl(2-sulfamoyl-6-benzothiazolyl)carbonate which melts at 144°-6° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][O:12][C:11]2[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:10]1=2>C(O)C.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:10]2[N:9]([CH2:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[C:14](=[O:15])[CH2:13][O:12][C:11]=2[CH:16]=1
Reactant: CN1CCCC1CCN1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CN1CCCC1CCN1C(=O)COc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 4-(2-(1-methylpyrrolidin-2-yl)ethyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.49 g, 1.604 mmol) in dry ethanol (5 mL) was treated with Pd—C (˜0.05 g) and purged with hydrogen gas. The flask was evacuated and purged twice with hydrogen gas. The reaction stirred at room temperature under hydrogen atmosphere (balloon pressure) for 2 hours. The reaction was filtered through a Celite bed and washed with methanol (3×10 mL). The combined organic layers were evaporated to obtain the crude title compound (0.44 g, quantitative) as a solid. 1H NMR (DMSO-d6) δ 1.39-1.51 (m, 2H), 1.56-1.66 (m, 2H), 1.76-2.06 (m, 4H), 2.16 (s, 3H), 2.88-2.94 (m, 1H), 3.74-3.86 (m, 2H), 4.46 (s, 2H), 5.01 (s, 2H), 6.22 (d, 1H, J=2.4 Hz), 6.26 (dd, 1H, J=2.1, 8.4 Hz), 6.82 (d, 1H, J=8.4 Hz); ESI-MS (m/z, %): 276 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])([O-:33])=[O:32]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N+:31]([O-:33])=[O:32])(=[O:41])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4[N+](=O)[O-])ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 26.1 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2-nitrobenzenesulfonyl chloride (44 mg, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was concentrated under reduced pressure. The residue was triturated with water (1 ml), filtered, and washed with of hexane:ethyl acetate (1:1). The crude product was chromatographed on silica gel, eluting with dichloromethane:methanol (399:1) to give the title compound (8 mg, 26%).