Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH2:12][CH3:13])[S:4]1(=[O:15])=[O:14].[Na].[SH:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[N:20][N:19]=1>CN(C=O)C>[C:23]1([N:22]2[C:18]([S:17][CH2:2][N:3]3[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH2:12][CH3:13])[S:4]3(=[O:15])=[O:14])=[N:19][N:20]=[N:21]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC1C(=O)N(CSc2nnnn2-c2ccccc2)S(=O)(=O)N1CC
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 1.96 mmol) and sodium salt of 5-mercapto-1-phenyl-1H-tetrazole (0.39 g; 1.98 mmol) (Formula III: M+ =Na+ ; X=S; R4 = ##STR24## in 10 ml of DMF was allowed to react at 80° C for 11 hours and then cooled. The mixture was poured into ice/water containing saturated sodium bicarbonate solution, extracted with ether/ethyl acetate (1:1; 250 ml), and the organic layer was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography (35% ethyl acetate in hexane) to afford 0.56 g (72%) of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: ##STR25## as an oil.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]2Cl)=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[C:30](O)(=[O:32])C>CO>[Cl:4][C:5]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]2[O:32][CH3:30])=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(=O)O
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
51.3 ml of a 2N solution of sodium methylate in methanol are added dropwise while stirring and cooling at 0° C. during 5 minutes to a solution of 42.4 g of isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate in 100 ml of absolute methanol. The reaction mixture is stirred at 0° C. for 10 minutes and adjusted to about pH 4 with concentrated acetic acid. Subsequently, the reaction mixture is evaporated to dryness under reduced pressure. The residue is dissolved in 300 ml of diethyl ether and the solution is washed twice with 100 ml of water each time. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (3:1) as the eluent and is subsequently recrystallized from n-hexane/diethyl ether. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate, m.p. 121°-123° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C([C@@H]1[C@H](N)C2[CH:30]=[CH:31][S:32]C=2CC1)CC>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[CH:30]=[CH:31][S:32][C:19]=3[CH2:18][CH2:17][C@@H:16]2[CH2:15][CH2:14][CH3:13])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC[C@H]1CCc2sccc2[C@H]1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.65, 7.05, 6.92, 5.68, 4.31, 2.97–2.80, 2.68, 2.53, 2.05, 1.97, 1.71, 1.51–1.25, 0.86; HRMS (FAB) calcd for C19H27N3S+H 330.2004, found 330.2001. Anal. Calcd for C19H27N3S: C, 69.26; H, 8.26; N, 12.75; S, 9.73. Found: C, 69.21; H, 8.28; N, 12.35.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][N:9]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 28c (3.1 g; 8 mmol) is suspended in acetonitrile (20 ml) under addition of N,N-diisopropyl ethyl amine (3.24 ml; 19 mmol). Methanesulfonylchloride (1.3 g; 11 mmol) is added and the mixture is stirred for 18 h at 25° C. The reaction mixture is evaporated to dryness and purified by silica gel chromatography. Yield: 3.5 g (102.5%), ESI-MS: m/z=450 [M−H]−
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(=O)(O)[O-].[Na+].[Cl:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])=[O:16]>O.CO>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][Cl:13])[CH:19]=1
Reactant: COC(=O)CN
Reactant: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CNC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a mixture of glycine methyl ester hydrochloride (358 g., 2.85 mole) and 2.4 l. of water is added sodium bicarbonate (239.4 g., 2.85 mole). After stirring at room temperature for 0.5 hr., the mixture is diluted with 1 l. of methanol, cooled at 0° C. while sodium bicarbonate (239.4 g., 2.85 mole) is added followed by portionwise addition of 3-(chloroacetylamino)benzoylchloride (650 g., 2.8 mole) during a 0.75 hr. period. Considerable foaming takes place when approximately one-half of the acid chloride has been added and is controlled by periodic addition of small quantities of methanol. The reaction mixture is stirred for 16 hrs., diluted with 800 ml. of water and then stirred for an additional 0.5 hr. to provide a solid which is collected and sequentially washed with 500 ml. of 50% methanol, 2 l. of water, and 500 ml. of 50% methanol. The washed material is first air dried for 3 days and then for 12 hrs. under reduced pressure at 45° C. to afford 626.7 g. (77% yield) of N-[3-(chloroacetylamino)benzoyl]glycine methyl ester, m.p. 122.0°-124.0° C. Analytically pure N-[3-(chloroacetylamino)benzoyl]glycine methyl ester is obtained by crystallization from methanol, m.p. 122°-127° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28](=O)[C:29]1[C:37]2[C:32](=[C:33]([CH2:38][O:39][Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:29]4[C:37]5[C:32](=[C:33]([CH2:38][O:39][Si:40]([CH:41]([CH3:43])[CH3:42])([CH:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:34]=[CH:35][CH:36]=5)[NH:31][CH:30]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)c1c[nH]c2c(CO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Product: CC(C)[Si](OCc1cccc2c(C3=C(c4ccc5c6c4ccn6CC(C(=O)OC(C)(C)C)NC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diaze-pino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and oxo-(7-triisopropylsilanyloxymethyl-1H-indol-3-yl)-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27]>C(#N)C>[ClH:25].[C:26]([O:29][CH2:30][C:31]([NH:1][C:2]1[C:3]([Cl:25])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][C:18](=[O:24])[OH:19])([CH3:15])[CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:32])(=[O:28])[CH3:27]
Reactant: CC(C)(CNc1c(N)c(Cl)nc2ccccc12)NC(=O)OC(C)(C)C
Reactant: CC(=O)OCC(=O)Cl
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(Cl)nc2ccccc2c1NCC(C)(C)NC(=O)O
Product: Cl
Temperature: 5 °C
Reaction time: 5 h

Procedure:
The solution of tert-butyl N-{2-[(3-amino-2-chloroquinolin-4-yl)amino]-1,1-dimethylethyl}carbamate in acetonitrile from Part C was cooled to 5° C. using an ice bath. A solution of acetoxyacetyl chloride (4.8 g, 35.1 mmol) in acetonitrile (20 mL) was added dropwise at a rate such that the temperature of the reaction mixture was maintained at 5° C. After the addition was complete the ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to provide 16.7 g of N-{2-[(3-acetoxyacetylamino-2-chloroquinolin-4-yl)amino]-1,1-dimethylethyl}carbamate hydrochloride as a yellow powder.
Reaction SMILES: N[C:2]1[C:3]2[C:27]3([CH2:31][CH2:30]OC3)[C:26](=[O:32])[NH:25][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:7]=1.N1CCCC[CH2:34]1>CC(C)=O.C(OCC)(=O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[CH:2][C:3]3[C:27](=[C:31]([CH3:34])[CH3:30])[C:26](=[O:32])[NH:25][C:4]=3[N:5]=2)=[N:9]1
Reactant: C1CCNCC1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C1(CCOC1)C(=O)N2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)=C1C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21

Procedure:
500 mg (1.388 mmol) of Example 4 were initially charged in acetone (50 ml), 0.274 ml (2.775 mmol) of piperidine was added and the mixture was heated under reflux for 1 h. After cooling, a precipitate was filtered off and washed with acetone, and the filtrate was concentrated under reduced pressure. This residue was then purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient). The material obtained in this manner was once more slurried in ethyl acetate, filtered off, washed with ethyl acetate and dried under high vacuum. This gave 101 mg of the title compound as a solid (18% of theory).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=[O:59])[C@@H:10]([NH:20][C:21](=[O:58])[CH2:22][CH2:23][C@@H:24]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:25][C:26](=[O:50])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:11]CC(OC(C)(C)C)=O.[NH2:60][C@H:61]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:62][CH2:63][C:64](=[O:66])[OH:65].Cl>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[C:70]([O:69][C:67](=[O:68])[C@@H:61]([NH:60][C:9](=[O:8])[CH2:10][CH2:11][C@@H:10]([C:9]([O:8][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:59])[NH:20][C:21](=[O:58])[CH2:22][CH2:23][C@@H:24]([C:51]([O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:52])[NH:25][C:26](=[O:50])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:62][CH2:63][C:64]([OH:65])=[O:66])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.8 %

Procedure:
(S)-2-[(S)-4-tert-Butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]-pentanedioic acid 5-tert-butyl ester 1-(2,5-dioxopyrrolidin-1-yl)ester (4 g, 4.77 mmol) was dissolved in acetonitrile (30 mL) and added to a solution of H-Glu-OtBu (1.07 g, 5.25 mmol) in Na2CO3 (0.1 M, 20 mL). The mixture was stirred at RT for 1 h, then neutralised with HCl (2M) to pH 7 and evaporated in vacuo. The residual oil was subsequently partitioned between ethyl acetate and HCl (0.1 M). The organic layer was dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue (4 g) was dissolved in acetonitrile and treated with active carbon. After filteration and evaporation to dryness followed by drying overnight in vacuo, 2.8 g of (S)-2-{(S)-4-tert-Butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}pentanedioic acid 1-tert-butyl ester was obtained as a crystalline solid. LC-MS (electrospray): m/z=927 (M+1).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:16])([F:15])[CH2:10][S:11](Cl)(=[O:13])=[O:12].[F:17][C:18]([F:53])([F:52])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[O:28][CH:29]=[C:30]([CH2:32][O:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH:48]=[CH:47][N:46]=[C:45]4[CH2:49][CH2:50][NH2:51])=[CH:36][CH:35]=3)[N:31]=2)=[CH:21][CH:20]=1.O>C1COCC1>[F:8][C:9]([F:16])([F:15])[CH2:10][S:11]([NH:51][CH2:50][CH2:49][C:45]1[N:44]([CH2:43][CH2:42][CH2:41][CH2:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]3[N:31]=[C:27](/[CH:26]=[CH:25]/[C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:53])([F:52])[F:17])=[CH:24][CH:23]=4)[O:28][CH:29]=3)=[CH:35][CH:36]=2)[CH:48]=[CH:47][N:46]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CC(F)(F)F)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 1.83 h

Procedure:
Triethylamine (137 μl) and 2,2,2-trifluoroethanesulfonyl chloride (65.0 l) were added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (250 mg) in THF (5 ml) at 0° C., and the mixture was stirred at the same temperature for 110 min. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex) (eluent; hexane:ethyl acetate=1:2 to 1:4) and recrystallized from ethyl acetate-methanol-hexane to give the titled compound (48 mg) as colorless needle crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:11]=1.CO[B:20](OC)OC.[CH3:25][C:26]([OH:32])([C:28]([CH3:31])([OH:30])[CH3:29])[CH3:27].B(O)O>C1COCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:10]1[CH:11]=[C:7]([B:20]2[O:32][C:26]([CH3:27])([CH3:25])[C:28]([CH3:31])([CH3:29])[O:30]2)[CH:8]=[N:9]1
Reactant: Brc1cnn(C2CCCCO2)c1
Reactant: COB(OC)OC
Reactant: CC(C)(O)C(C)(C)O
Agent: OBO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Temperature: -90 °C
Reaction time: 1 h

Procedure:
A solution of butyllithium (18.17 ml, 2.5M in hexanes) was added to 4-bromo-1-tetrahydropyran-2-yl-pyrazole, in solution in THF (400 ml) between −100° C. and −80° C. under nitrogen atmosphere. The mixture was stirred for 1 hour at −90° C. Trimethoxyborane (5.07 ml) was added at −70° C. and the mixture was stirred for a further 30 minutes. The mixture was quenched with a 15% solution of ammonium chloride (5 ml); the mixture was allowed to warm to room temperature and was stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with 20 ml of THF. The combined organic portions were dried over magnesium sulphate and the solvent was evaporated under reduce pressure to afford the crude boronic acid. 2,3-dimethylbutane-2,3-diol (5.11 g) was added to the boronic acid in solution in THF with 4 A molecular sieves (100 mg). The mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduce pressure. Water (5 ml) was added and the mixture was extracted with heptane (3×10 ml), dried over magnesium sulphate, filtered and evaporated under reduce pressure to afford 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (8.80 g). NMR Spectrum: (CDCl3) 1.31 (s, 1H), 1.54-1.76 (m, 4H), 1.95-2.17 (m, 2H), 3.66-3.73 (m, 1H), 4.01-4.07 (m, 1H), 5.41 (dd, 1H), 7.82 (s, 1H), 7.94 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4].C(N(CC)CC)C.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4]
Reactant: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
5-Methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester (24.0 g, 100 mmol) prepared in Preparation 15 was dissolved in dichloromethane (500 mL), to which were added triethylamine (84 mL, 601 mmol) and 4-(dimethylamino)pyridine (600 mg, 5 mmol). (BOC)2O (43.7 g, 200 mmol) dissolved in dichloromethane (100 mL) was added in drops thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (34.0 g, Yield 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:1][C:2]1[C:7]([C:8]([O:10][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 2-c, (1 g, 4.85 mmol) in DMF (40 ml) was added K2CO3 (2.34 g, 16.98 mmol) and benzyl bromide (1.83 g, 10.67 mmol). The mixture was heated at 70° C. for 16 hours. The solution was then cooled to room temperature and diluted with water followed by extraction with ethyl acetate. The combined organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum to provide the crude product, 2-d, as a solid (1.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:23][C:24]([CH3:26])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 221.5 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 188d (1.2 g, 3.3 mmol), and acetone (1.0 g, 16.5 mmol) in methanol/acetic acid (30 mL/3 mL) was stirred for 5 minutes at room temperature, followed by the addition of NaBH(OAc)3 (3.5 g, 16.5 mmol). The mixture was stirred at 50° C. for 2 h. It was cooled to room temperature and H2O (50 mL) was added. The mixture was extracted with DCM (50 mL) three times. The organic layers were concentrated under reduced pressure and the residue was purified by column chromatography eluting with 25:1 DCM/methanol to give 220a (2.97 g, 81%). MS: [M+H]+ 406. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=3.0, 1H), 8.53 (s, 1H), 7.92 (d, J=3.0, 1H), 7.44 (d, J=2.5, 1H), 7.37 (d, J=2.5, 1H), 7.25 (d, J=8, 1H), 3.51 (s, 3H), 3.06 (t, J=4.5, 4H), 2.69 (s, 1H), 2.57-2.50 (m, 4H), 1.00 (d, J=7, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Reaction time: 2 h
Yield: 83 %

Procedure:
(4-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.91 g, 8.51 mmol) was dissolved in dry DMSO (10 mL) and the reaction flask immersed in a waterbath at 15° C. Triethylamine (1.72 g, 17.0 mmol) was added followed by sulfur trioxide pyridine complex (2.41 g, 15.1 mmol). The reaction mixture was stirred for 2 h and poured onto crushed ice and the product extracted with CHCl3. The organic extract was washed with water, dried concentrated under reduced pressure. The crude product was purified by flash chromatography (hexane/EtOAc, 80:20) to give (4-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.57 g, 83%).
Reaction SMILES: OCCNS([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)(=O)=O.ClC1C=CC([NH2:22])=CC=1C1C=CC=CN=1>>[C:12]([NH2:22])(=[O:13])[C:11]1[CH:15]=[CH:16][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCCO)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: NC(=O)c1ccccc1

Procedure:
Procedure G was used to couple 4-(2-hydroxyethylsulfamoyl)benzoic acid with 4-chloro-3-(pyridin-2-yl)aniline (42 mg) to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(2-hydroxyethyl)amino]sulfonyl]-benzamide. MS (Q1) 431.9 (M)+.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]([OH:10])=O)[CH2:6][O:5][C:4](=[O:7])[O:3]1.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>ClCCl>[CH3:1][C@@:2]1([C:8]([Cl:14])=[O:10])[CH2:6][O:5][C:4](=[O:7])[O:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@]1(C(=O)O)COC(=O)O1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@]1(C(=O)Cl)COC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound prepared in Example 184 (330 mg) in dichloromethane (11 mL) were added oxalyl chloride (290 μL) and DMF (0.1 mL) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuum condition to give the title compound (2.0 g) having the following physical data as a coarse product. This compound was used for the next reaction without being purified.