Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cc(OC4CCCCC4)ccc32)cc1

Procedure:
(18.7 mg, 51%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.6 mg, 0.082 mmol) and 4-methoxybenzoyl chloride (30 uL, 0.20 mmol); HRMS-FAB+ for C28H32N2O3 : calculated MH+ : 445.2491 1; found: 445.25149.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[C:10]([OH:23])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][C@@H:2]1[N:3]([C:9]2[C:10](=[O:23])[NH:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:5][O:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of (3S)-3-methylmorpholine (127 mg, 1.26 mmol) in DMSO (2 mL) was added methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (200 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol). The resulting solution was stirred at 70° C. for 3 h and then quenched by water (10 mL). The solids were collected by filtration to afford (S)-methyl 3-(3-methylmorpholino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, crude).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CS(O[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[C:8]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CCC2
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2c(n1CCCCOC)C(=O)CCC2
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A solution of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (207 mg), 4-methoxybutyl methanesulfonate (273 mg) and cesium carbonate (652 mg) in N,N-dimethylacetamide (10 ml) was stirred at 60° C. for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml×2). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (250 mg).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:14][CH:13]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3cccc(C(F)(F)F)c3)c(=O)c2=O)cc1
Yield: 67.8 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 3-trifluoromethylphenethyl-amine (0.23 g, 1.22 mmol) in ethanol (3 mL) were converted to the title compound (0.155 g, 68%) m.p.: 220.2-222.3° C.; 1H NMR (DMSO-d6) δ9.05(br t,1H), 7.95(ABq,2H), 7.60-7.45(m,4H), 7.08(ABq,2H), 3.94(br t,2H), 3.83(s,3H), 3.04(t,3H); IR (KBr) 3210, 3170, 1775, 1780, 1575, 1360, 1325, 1175, 1125, 1070, 1020, 840, 800, 695 cm−1; MS (m/z) 375 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][N:4]=1
Reactant: Nc1ccnnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A stirred suspension of 2.6 grams (0.027 mole) of 4-aminopyridazine (prepared as in Example 1, Step A) in 100 ml of tetrahydrofuran is cooled to 0° C. and 4.6 ml (0.033 mole) of triethylamine is added in one portion. A solution of 4.1 ml (0.033 mole) of phenyl chloroformate in tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition the reaction mixture is allowed to warm to ambient temperature where it is stirred for three days. The reaction mixture is concentrated under reduced pressure to a residue. The residue is taken up in 500 ml of chloroform and filtered to collect 1.9 grams of phenyl N-(4-pyridazinyl)carbamate; m.p. 184°-185° C. The filtrate is washed with water, then dried with magnesium sulfate. The mixture is filtered and the filtrate placed on a column of silica gel. Further elution is accomplished using 10% methanol in methylene chloride. The appropriate fractions are combined and concentrated under reduced pressure to yield an additional 1.8 grams of phenyl N-(4-pyridazinyl)carbamate. The nmr spectra are consistent with the proposed structure. The reaction is repeated several times.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH:2]([CH3:1])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCC(=O)c1ccc(OCC(=O)OC)cc1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of RS methyl 4-(2-methylacetyl)phenoxyacetate (1.2 g) in acetonitrile (10 ml) was added dropwise over 30 minutes to a stirred solution of 1-(4-pyridyl)piperazine (1.3 g) in acetonitrile (30 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate evaporated to give an oil. Purification by flash chromatography, eluting first with dichloromethane then successively 2.5%, 3%, 4%, 5% and 10% v/v methanol/dichloromethane gave the title compound, 220 mg as a solid: m.p. 81°-83° C.; NMR (d6DMSO) δ8.13(2H,d), 8.06(2H,d), 7.02(2H,d), 6.77(2H,d), 4.92(2H,s) 4.33(1H,q), 3.72(3H,s), 3.26(4H,t), 2.63(4H,t), 1.16(3H,d); m/e 384(M+H)+ ; calculated for C21H25N3O4 : C, 65.8; H, 6.6; N, 11.0. found C, 65.7; H, 6.8; N, 10.9%.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (250 mg) of methylamine were added to 1(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), arid the mixture was heated and stirred overnight at 70° C. After the solvent was distilled off under reduced pressure, and ethanol (2 ml) and acetic acid (1 drop) were added to the residue to stir the mixture, solids deposited were collected by filtration and washed successively with ethanol and diethyl ether to obtain the title compound (51 mg) as a pale brown powder.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].[N:31]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:35]([N:31]2[CH2:34][CH2:33][CH2:32]2)(=[O:37])=[O:36])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: O=S(=O)(Cl)N1CCC1
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)N2CCC2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A flask was charged with (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.200 g, 0.471 mmol, Example #8, Step M) and DMF (4 mL). The solution was cooled to about 0° C. followed by the addition of TEA (0.16 mL, 1.2 mmol) and azetidine-1-sulfonyl chloride (0.165 g, 1.06 mmol, Preparation #CC.1). The reaction mixture was warmed to ambient temperature and was stirred for about 2 h. The solvent was removed under reduced pressure and DCM (10 mL) was added to the resulting residue. The organic solution was washed with water and brine (5 mL each). The combined organics were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to afford N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl)azetidine-1-sulfonamide (0.20 g, 77%) as a white solid: LC/MS (Table 1, Method a) Rt=2.39 min; MS m/z: 544 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]([O:47][CH2:48][C@@H:49]([NH:66][CH3:67])[C:50]([N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:66]([C@@H:49]([C:50](=[O:51])[N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:48][O:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:67])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.12 g; 0.49 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.49 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.1 g; 0.51 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-Benzyloxy-N-methyl-2-(methyl-amino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-propionamide (0.17 g; 0.44 mmol) and diisopropylethylamine (0.084 mL; 0.49 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was extracted with an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2.5×30 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.275 g of ((3E)-4-(N-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](=[O:6])[NH:2]1.N1C=CC=CC=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:1]1[CH:5]=[CH:4][C:3](=[O:6])[NH:2]1)(=[O:15])[CH3:14]
Reactant: O=c1cc[nH][nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)n1ccc(=O)[nH]1
Temperature: 95 °C

Procedure:
A mixture of 1,2-dihydro-3H-pyrazol-3-one (4.50 g, 26.8 mmol), in pyridine (20.4 mL, 252 mmol) was heated to 95° C. then charged with a solution of acetic anhydride (5.10 mL, 54.0 mmol) in pyridine (9.64 mL, 119 mmol) over a 15 min period. The reaction was heated for an additional 1 h at 95° C. The reaction mixture was concentrated in vacuo resulting in a dark red oil which was triturated with MeOH and filtered resulting in the title compound as a light yellow solid. A 2nd crop of product was isolated from the mother liquors. 1H NMR (400 MHz, DMSO-d6): δ=2.48 (s, 3H) 6.00 (d, J=3.0 Hz, 1H), 8.12 (d, J=3.0 Hz, 1H), 10.95 (br. s., 1H). MS (ES+): m/z 127.23 (100) [MH+]. HPLC: tR=0.82 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:29][CH:28]=1)=[O:26])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (67.5 mg, 57%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH2:9][CH2:8]1
Reactant: COCCN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN1CCN(S(=O)(=O)c2cccs2)CC1
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
To a suspension of 1-(2-methoxyethyl)piperazine dihydrochloride (2.61 g, 12.0 mmol) in THF (100 mL) was added triethylamine (10 mL) and the resulting mixture was stirred for 10 min. Then a solution of 2-thiophenesulfonyl chloride (1.98 g, 10.84 mmol) was added in THF (3 mL) over 5 min. The reaction mixture was allowed to stir at room temperature for 1 h, the volatiles were evaporated and the residue was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with a saturated sodium bicarbonate solution (50 mL), brine and dried over molecular sieves. Evaporation to dryness gave a viscous oil (2.09 g, 75%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:31])[C:17]([N:22]3[CH2:25][C:24]4([CH2:29][CH2:28][CH2:27][N:26]4[CH3:30])[CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][C:24]4([CH2:29][CH2:28][CH2:27][N:26]4[CH3:30])[CH2:25]3)=[C:16]([NH:31][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A solution of acryloyl chloride (5.71 mg, 0.06 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)benzene-1,3-diamine (Intermediate 45, 31 mg, 0.06 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 gave the title compound (21 mg, 61%) as a yellow foam; 1H NMR: 1.70 (2H, dd), 1.98-2.11 (2H, m), 2.37 (3H, s), 2.62 (2H, t), 3.65 (2H, d), 3.76 (3H, s), 3.95 (2H, d), 5.67 (1H, d), 6.09-6.27 (2H, m), 6.43 (1H, dd), 7.10 (1H, t), 7.30 (1H, s), 7.34-7.45 (1H, m), 8.35 (2H, s), 8.44 (1H, s), 8.81 (1H, d), 8.92 (1H, s), 9.20 (1H, s); m/z: ES+ MH+ 545.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20](NC2C=C(C(O)=O)NC=2)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.[N+](C1C=C(C(O)=O)NC=1)([O-])=O.[F:48][C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[CH:51][C:50]=1[N+:58]([O-])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:58][C:50]2[CH:51]=[C:52]([CH:56]=[CH:57][C:49]=2[F:48])[C:53]([OH:55])=[O:54])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1c[nH]c(C(=O)O)c1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(O)c1cc([N+](=O)[O-])c[nH]1
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cc(C(=O)O)ccc1F

Procedure:
Instead of the starting material compound of Example 262, that is, 4-nitropyrrole-2-carboxylic acid, 4-fluoro-3-nitrobenzoic acid was used for the similar procedure as in Example 262 to obtain the title compound.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(OCC)C>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)N(NS(=O)(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
N'-t-butyl-N'-benzoylhydrazine (0.4 g) was stirred in pyridine (3 ml) at room temperature. Benzenesulfonyl chloride (0.5 g) was added slowly, dropwise and stirred for 2 hours, diluted with diethyl ether (20 ml) and washed several times with a 10% HCl solution and then water. The organic layer was dried over magnesium sulfate, filtered and the solvent rotavapped off to afford a white solid in good yield.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=4)[CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:13][C:8]=3[N:7]([CH3:29])[S:6]2(=[O:31])=[O:30])[CH2:3][CH2:2]1.C(Cl)[Cl:33].Cl.CCOC(C)=O>CO>[ClH:33].[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[C:16]([CH2:17][NH2:18])[CH:26]=[CH:27][CH:28]=4)=[CH:13][C:8]=3[N:7]([CH3:29])[S:6]2(=[O:30])=[O:31])[CH2:3][CH2:2]1
Reactant: CN1c2cc(-c3cccc(CNC(=O)OC(C)(C)C)c3)ccc2N(CC2CC2)S1(=O)=O
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1c2cc(-c3cccc(CN)c3)ccc2N(CC2CC2)S1(=O)=O
Temperature: 25 °C

Procedure:
To a round bottom flask was added tert-butyl {3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]benzyl}carbamate (23-1) (0.250 g, 0.564 mmol), DCM (2 mL), MeOH (2 mL), and finally a saturated solution of HCl in EtOAc (4N) (0.705 mL, 2.82 mmol). The reaction mixture was then capped and permitted to stir at room temperature for an hour at which point it was concentrated to give 1-{3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]phenyl}methanamine hydrochloride (23-2) as a waxy pink solid. HRMS (M+H)+: observed=344.1429, calculated=344.1427.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH3:35])([CH3:34])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26](OCC)=[O:27])C>C(OC)(C)(C)C>[CH3:34][C:11]([CH3:35])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][OH:27])[CH2:10][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCCC(=O)CCCCCCC(C)(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CC(C)(CO)CCCCCCC(O)CCCCCCC(C)(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
Under N2-atmosphere, methyl tert-butyl ether (MTBE, 80 mL) was added to LiAlH4 (0.67 g, 17.65 mmol) and the suspension was stirred under cooling with an ice-water bath. A solution of 209i (3.0 g, 7.03 mmol) in MTBE (20 mL) was added dropwise, followed by additional MTBE (40 mL). After 2 h at 0° C., the reaction mixture was carefully quenched by addition of ethyl acetate (8 mL) and allowed to warm to room temperature overnight. The mixture was cooled with an ice-water bath and carefully hydrolyzed by addition of crushed ice (15 g) and water (15 mL). The pH was adjusted to 1 by addition of 2 N aqueous sulfuric acid (28 mL) and the solution was stirred at room temperature for 15 min. The layers were separated and the aqueous layer was extracted with MTBE (40 mL). The combined organic layers were washed with deionized water (50 mL), saturated NaHCO3 solution (40 mL), and brine (40 mL), dried over anhydrous MgSO4, concentrated in vacuo and dried in high vacuo. The crude product (2.65 g) was purified by recrystallization from hot CH2Cl2 (20 mL). The crystals were filtered, washed with ice-cold CH2Cl2 (20 mL) and dried in high vacuo to furnish 211i (1.59 g, 66%) as a white solid. Mp 75-77° C. 1H NMR (CDCl3): δ (ppm): 3.57 (m, 1H), 3.30 (s, 4H), 1.72 (br, 2H), 1.50-1.16 (m, 25H), 0.85 (s, 12H). 13C NMR (CDCl3): δ (ppm): 72.09, 38.79, 37.61, 35.21, 30.70, 29.85, 25.78, 24.06, 23.92. HRMS (LSIMS, gly): Calcd for C21H45O3 (MH+): 345.3369. found: 345.3364. HPLC: 95.0% pure.