Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Yield: 84.7 %

Procedure:
3.335 g (14.5 mmol) of 6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione was dissolved in 65 mL of conc. H2SO4 with stirring and cooling in an ice-H2O bath, then 2.20 g (21.76 mmol) of KNO3 (Baker, used as received) was added in portions over 10 min. with stirring. The resulting mixture was stirred at 22° C. under N2 for 20 h. then was slowly poured into ice-H2O (400 mL) with stirring. The precipitate was collected on a sintered funnel by vacuum filtration, washed with H2O (5×10 mL), and dried at 60° C. under 0.1 mmHg for 12 h affording 3.39 g (85%) of the crude 6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione as a grey-yellow powder. Purity: >98.5% based on HPLC analysis.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24](O)=[O:25])[C:14]4=[O:31])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([NH:32][C:33]3[CH:37]=[CH:36][O:35][N:34]=3)=[O:25])[C:14]4=[O:31])[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(CC4CC4)CC3)cc2c1=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(CC4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 0.02 (m, 2H), 0.37 (m, 2H), 0.77 (m, 1H), 2.08 (s, 3H), 2.13 (m, 2H), 2.51 (m, 4H), 3.19 (m, 4H), 6.95 (s, 1H), 7.38 (s, 1H), 7.52 (m, 3H), 7.96 (m, 2H), 8.03 (s, 1H), 8.76 (s, 1H), 11.36 (s, 1H); Mass Spectrum: M+H+ 485.
Reaction SMILES: C(Cl)CCl.[CH2:5]([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]([OH:24])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.O[NH:36][C:37](=[NH:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH2:5]([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:24][N:43]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCOC(=O)C(=N)NO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
EDC (0.916 g, 4.78 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1.2 g, 4.34 mmol) and HOBt (0.732 g, 4.78 mmol) in DMF (12 mL) at rt. The mixture was stirred at rt for 0.5 h, then ethyl 2-(hydroxyamino)-2-iminoacetate (0.689 g, 5.21 mmol) was added and the mixture was stirred for another 0.5 h at rt. The reaction mixture was then heated to 100° C. under microwave for 80 minutes. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0 to 5% MeOH/DCM) to afford ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (0.85 g, 53%). ESI-MS (EI+, m/z): 373.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].[CH3:26][N:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:7]2[CH2:8][CH2:9][N:10]([C:28]([N:27]([CH3:26])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH2:11][CH:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=1)[C:23]#[C:24][CH3:25]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N(C)c3ccccc3)CC2C(=O)OCC)cc1
Yield: 98 %

Procedure:
In the same manner as described in Step 1 of Example 215, the 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester (1.0 g, 2.7 mmol) was treated with N-methyl-N-phenylcarbamoyl chloride to provide 1.33 g (98%) of ethyl 1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-piperazinecarboxylate as a brown oil. Electrospray Mass Spec 500.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=12.[I:12]N1C(=O)CCC1=O.CN(C=O)C>C(OCC)(=O)C.C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[I:12][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccn2ccnc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccn2c(I)cnc2c1
Reaction time: 2 h

Procedure:
In a 50 mL round-bottomed flask, imidazo[1,2-a]pyridine-7-carbonitrile (1.1 g, 7.68 mmol) and N-iodosuccinimide (2.07 g, 9.22 mmol) were combined with DMF (50 ml) to give a colorless solution. The reaction mixture kept at 20° C. and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (150 ml), THF (50 ml) and 300 ml of 5% sodium thiosulfate and well shaken. The aqueous layer was back-extracted with ethyl acetate (1×100 mL). The organic layers were combined, washed with water, brine, dried (MgSO4) and evaporated. The crude material was purified by flash chromatography (silica gel, 60% to 80% ethyl acetate/hexanes) to give 3-iodo-imidazo[1,2-a]pyridine-7-carbonitrile. 1H NMR (300 MHz, DMSO-d6) δ: 8.52 (d, 1H) 8.44 (d, 1H) 8.04 (d, 1H) 7.36 (dd, 1H).
Reaction SMILES: CC([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])CO.C(C(CCCCCCCCCCCC)[CH2:21][OH:22])C>>[CH2:12]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:21][OH:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCC(C)CO
Reactant: CCCCCCCCCCCCC(CC)CO
Product: CCCCCCC(CO)CCCCCC

Procedure:
2-methyl-1-pentadecanol; 2-ethyl-1-tetradecanol;
Reaction SMILES: [OH:1][C:2]1[N:7]2[C:8]([SH:11])=[N:9][N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[K+]>O>[C:12]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[C:8]([SH:11])=[N:9][N:10]=[C:6]2[N:5]=1)([OH:14])=[O:13]
Reactant: COC(=O)c1cc(O)n2c(S)nnc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(O)n2c(S)nnc2n1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
The product obtained in Step 1 (4.5 g) was added to a solution of 1.7 g potassium hydroxide in 50 ml water, and the mixture was refluxed for two hours. After cooling to room temperature, the solution was washed with 50 ml of ethyl acetate, the pH was adjusted to 1.0 with hydrochloric acid, and the formed crystals were collected by filtration, affording 3.9 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]([C:19]([OH:21])=O)[CH2:10][CH2:9]1.C[N:23](CC1C=CC(N)=CC=1)C1CCOCC1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=N>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]([C:19]([NH2:23])=[O:21])[CH2:10][CH2:9]1
Reactant: Cc1ncsc1CN1CCC(C(=O)O)=Cc2ccccc21
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CN(C)CCCN=C=N
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncsc1CN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A catalytic amount of N,N-dimethyl-4-aminopyridine was added to a solution of 7-butoxyethoxyphenyl)-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (150 mg), 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (88 mg) and 1-hydroxybenzotriazole (96 mg) in DMF (15 ml), followed by addition of 1-ethyl-3-(3-dimethylaminopropylcarbodiimide (137 mg). The mixture was stirred under nitrogen atmosphere at room temperature overnight. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-tetrahydropyran-5-yl)amino]methyl]phenyl]-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 81) (7 mg) as yellow amorphous.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:45][CH2:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](Cl)=[O:50]>>[Cl:45][CH2:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:50]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3CCl)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with 2-chloromethyl-benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-chloromethyl-benzoyloxy)-ethoxy]-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless solid; MS: 776 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[S:10]1[C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]1=2
Reactant: O=[N+]([O-])C=Cc1cc2ccccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1cc2ccccc2s1
Yield: 90.3 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 2, 2-(2-nitro-vinyl)-benzo[b]thiophene (I-9a: 2.1 g, 0.010 mol) in dry THF (30 mL) was reacted with LAH (0.81 g, 0.021 mol) in dry THF (20 mL) to afford 1.6 g of the product (87.91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:34][CH2:35][CH2:36]O)[CH2:31][CH2:32][CH3:33].Cl>>[ClH:1].[CH2:16]([O:17][CH2:18][CH2:20][O:24][C:23]([C:18]1([C:20]([O:22][CH2:36][CH2:35][O:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH2:15][CH2:14][CH3:13]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CCCCOCCO
Agent: Cl
Product: CCCCOCCOC(=O)C1(C(=O)OCCOCCCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-butoxyethanol accord-ing to the procedure of Example 1 as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 0.78-0.93 (m, 6H), 1.15-1.78 (m, 12H), 2.70-3.62 (brm, 5H), 3.31-3.47 (m, 4H), 3.57-3.73 (m, 4H), 4.29-4.53 (m, 4H), 5.47-5.57 (brs, 1H), 6.70-6.95 (m, 3H), 7.20-7.49 (m, 4H); MS (ES) m/z (relative intensity): 622 (M+ -HCl, 20), 214 (10), 158 (10).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: Cc1ccc(I)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(I)ccc1C
Temperature: 50 °C

Procedure:
A solution of 5-iodo-2-methyl-phenylamine (20.4 g, 87.6 mmol) in 200 mL of dry CH2Cl2 was cooled to 0° C. and acetic anhydride (16.5 mL, 175 mmol) was added dropwise. The mixture was heated to 50° C. for 2 h and then cooled to 22° C. The resulting white precipitate was filtered to give c (18.4 g, 76%): MS m/z=276 (M+H).
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:25]=[O:26].O>CCCCCC.C1COCC1>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:25]=[O:26])=[CH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-Butyllitium in hexane (95 ml, 1.55M) was added dropwise to 4-Bromo-4'-trifluoromethylbiphenyl (40 g) in 250 ml of THF under N2 at -70° C. After addition the mixture was stirred for a further 10 mins and then dry dimethylformamide (19.49) in a solution of dry tetrahydrofuran (100 ml) was added dropwise. The mixture was then allowed to warm to room temperature in the absence of coolant. After stirring for 1.5 hours water was added and the mixture extracted with ether. The water washed and dried extracts were evaporated to give p-(4-trifluoromethylphenyl)benzaldehyde (34.5 g) m.p. 70°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:22]3[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]3=[N:24][CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([F:61])[CH:60]=1)[CH2:41][N:42]1[C:46]([CH3:47])=[C:45](B2OC(C)(C)C(C)(C)O2)[C:44]([CH3:57])=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:22]3[C:28]([C:45]4[C:44]([CH3:57])=[N:43][N:42]([CH2:41][C:40]5[CH:58]=[C:59]([F:61])[CH:60]=[C:38]([F:37])[CH:39]=5)[C:46]=4[CH3:47])=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]3=[N:24][CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)ccc1F)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(F)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c3)cc12
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-fluorophenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 66A)(85 mg, 0.134 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (93 mg, 0.269 mmol) using sodium carbonate (43 mg, 0.404 mmol) and Pd(PPh3)2Cl2 (5 mg, 0.006) in DME/water (20/4 mL) to afford 89 mg of the crude compound. MS: m/z=670.2 (M+1) (de boc mass observed).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reaction time: 8 h

Procedure:
770 mg (3.83 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 467 mg (3.83 mmol) of 4-hydroxybenzaldehyde were dissolved in 20 ml of THF. 1.2 g (4.6 mmol) of triphenylphosphine and 790 mg (4.6 mmol) of N,N,N′,N′-tetramethylazodicarboxyamide were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[S:10][C:5]=2[C:4](=[O:17])[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>O1CCCC1>[Cl:28][C:29]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:7]1[C:6]2[N:8]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[S:10][C:5]=2[C:4](=[O:17])[N:3]=[C:2]1[CH3:1]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: Cc1nc(=O)c2sc(N3CCOCC3)nc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (75 mg, 0.297 mmol) in Tetrahydrofuran (THF) (1.5 mL) was stirred at 0° C. for 15 min, then lithium bis(trimethylsilyl)amide (446 μl, 0.446 mmol, 1.0 M in THF) was added and stirring was continued for 30 min. 2,3-Dichlorobenzyl bromide (86 mg, 0.357 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. Additional stirring at 65° C. for 2 h completed the reaction resulting in a mixture of the desired product and the regio-isomer. The reaction was concentrated and the residue was purified by reversed-phase HPLC to provide the product, 4-[(2,3-dichlorophenyl)methyl]-5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (28 mg, 23%). LC/MS: MS (ES+) m/e 411 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 3.52 (m, 4H) 3.64-3.72 (m, 4H) 5.60 (s, 2H) 6.90 (d, J=7.3 Hz, 1H) 7.33 (m, 1H) 7.64 (d, J=8.0 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:20]([C@@H:19]2[NH:18][C@@H:17]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[C@H:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Br)c2F)c(OC)c1
Yield: 51.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.64 mmol), was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.18 g, 0.99 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield 0.22 g, 51%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[Br:17][C:13]1[CH:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2cccc(Br)c2)cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3 (0.5 g, 1.7 mmol) in methanol (25 mL) was added aqueous NaOH (2M; 4.3 mL) and the reaction mixture was stirred at 40° C. for 0.5 h. Methanol was removed in vacuo and the water layer acidified and extracted with ethyl acetate, dried, filtered and evaporated to dryness. The crude compound was used as such for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([S:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=4)(=[O:36])=[O:35])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCC1(CC)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Product: CCC1(CC)C(=O)N(C2CCN(S(=O)(=O)c3cccc(C)c3)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B7) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:35][C:32]3[S:33][CH:34]=[C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[N:31]=3)=[O:19])=[C:16]([F:23])[CH:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1F
Reactant: Nc1nc(-c2ccccn2)cs1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1F

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluorobenzoic acid (9) (160 mg, 0.48 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (70 mg, 0.40 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluoro-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 38 mg (19%). 1H-NMR: 8.63-8.60 (m, 1H), 7.98-7.85 (m, 4H), 7.61 (d, J=8.5 Hz, 2H), 7.52 (dd, J=8.5, 2.0 Hz, 1H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.26-7.20 (m, 1H), 7.15-7.12 (m, 2H), 3.87-3.82 (m, 2H), 2.51-2.47 (m, 2H), 1.71-1.63 (m, 2H).