Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([CH3:39])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([CH3:39])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Product: Cc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-N-(2-hydroxy-ethyl)-2-methyl-benzenesulfonamide (example B.17) (267 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 41%). MS (ISP) 551.3[(M+H)+]; mp 184–186° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C#N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-cyanopyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica gave 280. NMR (CDCL3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.38 (1H, s), 7.80 (1H, d, J=8.1), 8.84 (1H, d, J=8.2), 9.75 (1H, s). MS (ESI+): MH+541.30 (50%)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32]>O1CCOCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[O:17])#[N:2]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Reactant: COCCCN
Solvent: C1COCCO1
Product: COCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Temperature: 80 °C
Yield: 74.7 %

Procedure:
A mixture of phenyl (4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)carbamate (37 mg, 0.10 mmol) and 3-methoxypropylamine (0.015 mL, 0.15 mmol) in 0.8 mL dioxane was heated at 80° C. After 2 hours the reaction mixture was evaporated to a solid film. The solid was triturated with dichloromethane and then 10% EtOAc in hexane to give a yellow-orange solid. This material was then chromatographed eluting with gradient 50% to 70% EtOAc in hexane. The filtrate from trituration and material from another reaction were combined and chromatographed with EtOAc/hexane. The clean product lots were combined to give the title compound as an off-white solid (27 mg).
Reaction SMILES: [NH:1]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:2]([NH2:4])=[S:3].C(N(CC)C(C)C)(C)C.Br[CH:23]([CH:26]=O)[CH:24]=[O:25]>C1COCC1>[CH:24]([C:23]1[S:3][C:2]([NH:1][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:4][CH:26]=1)=[O:25]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)CNC(N)=S
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the crude product from Example 1 in anhydrous THF (200 mL) is added N,N-diisopropylethylamine (25 mL, 143 mmol) followed by 2-bromomalonaldehyde (18.5 g, 123 mmol). The resulting mixture is allowed to stir at room temperature for 18 h, heated to 70° C. for 6 h, and then stirred at room temperature for an additional 18 h. The solvent is removed in vacuo and the residue is partitioned between EtOAc (400 mL) and water (350 mL). The water layer is back extracted with EtOAC (300 mL), the organic layers are combined, washed with brine (1×200 mL), dried over Na2SO4, filtered and the solvent removed in vacuo. The residue is purified by BIOTAGE® Silica gel chromatography on a 300 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 45% EtOAc/CH2Cl2 over 8 column volumes to give 3.5 g (17%, 2 steps) of the title compound as a tan solid. LC/MS (Condition A): ret. T=2.66 min, (M+Na) 265.09. 1H NMR (500 MHz, chloroform-d) δ ppm 9.73 (1 H, s), 7.86 (1 H, s), 4.05 (2 H, s), 1.49 (9 H, s).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 17) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (4.9 mg, 10% for the last two steps)
Reaction SMILES: [CH3:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23](=[O:44])[NH:24][C:25]([C:27]1[S:28][C:29]([S:42][CH3:43])=[C:30]([S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=2)(=[O:34])=[O:33])[CH:31]=1)=[NH:26])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:44])[NH:24][C:25]([C:27]1[S:28][C:29]([S:42][CH3:43])=[C:30]([S:32]([C:35]2[CH:36]=[C:37]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:8])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:31]=1)=[NH:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cccc(N)c1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Yield: 27.6 %

Procedure:
The procedure described in Example 1: step c was followed using 3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (95 mg. 0.41 mmol, Example 25: step b), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100.7 mg, 0.21 mmol, Example 27: step c), Pd(PPh3)4 (47 mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the residue yielded the title compound (30 mg, 28%) as an off-white solid. ESI-MS (m/z): Calcd. For C24H27N3O4S3: 517.2; found: 517.8.
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([NH2:71])[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:73]1([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH:78]=[CH:77][C:76]([CH:79]2[CH2:83][CH:82](OC)O[CH:80]2OC)=[CH:75][CH:74]=1.FC(F)(F)C(O)=O.C(OC(=O)[C@H](N1C=CC(C2C=CC(C3C=CC=CC=3)=CC=2)=C1)CC(N[C@H](C(=O)N(OC)C)CC(C)C)=O)C1C=CC=CC=1>ClCCCl>[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([N:71]1[CH:82]=[CH:83][C:79]([C:76]2[CH:77]=[CH:78][C:73]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[CH:74][CH:75]=2)=[CH:80]1)[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:63])[CH3:64])=[O:58])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Agent: CON(C)C(=O)[C@H](CC(C)C)NC(=O)C[C@H](C(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18), 12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3 (R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3) δ 7.62 (d, 2H, J=7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J=7.7 Hz), 7.35-7.21 (m, 7H), 7.10 (s, 1H), 6.80 (t, 1H, J=2.2 Hz), 6.60 (bs, 1H), 5.17-1.13 (m, 1H), 5.10 (s, 2H), 4.97-4.92 (m, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J=5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J=8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J=6.25 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C35H39N3O5: C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2/[CH:11]=C\C(OCC)=O)[CH:4]=[CH:3][CH:2]=1.[O:18]=[O+][O-]>ClCCl.CO>[N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2[CH:11]=[O:18])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C\c1cncc2cccnc12
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cncc2cccnc12
Temperature: 25 °C

Procedure:
A solution of ethyl (2Z)-3-(1,6-naphthyridin-8-yl)prop-2-enoate (30 g) in dichloromethane (500 mL) and methanol (125 mL) was cooled to −78° C. and reacted with ozone until the color of the reaction mixture became light blue (˜3 h). The reaction was purged with nitrogen to remove the residual ozone. Methyl sulfide (60 mL) was then added, and the reaction was allowed to warm to room temperature and then concentrated. The resulting residue was dissolved in dichloromethane (300 mL), washed with water (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and dried over sodium sulfate. The solvent was removed and product was slurried in heptane/ethyl acetate mixture (5:1). The solid was then filtered and dried under reduced pressure to provide the title compound: LCMS m/z 158.97 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.39 (s, 1 H), 9.09 (s, 1 H), 9.13 (m, 1 H), 9.07 (s, 1 H), 8.43 (d, J=8.3 Hz, 1 H), 7.78 (dd, J=8.7, 4.8 Hz, 1 H), 7.63 (dd, J=8.2, 4.2 Hz, 1 H), 7.34 (dd, J=8.7, 2.2 Hz, 1 H), 7.07 (m, 1 H), 3.55-3.53 (m, 1 H), 0.62-0.61 (m, 4 H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH3:24][C:25]1([O:28][CH2:27]1)[CH3:26]>O>[CH3:24][C:25]([OH:28])([CH3:27])[CH2:26][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:7]3[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Reactant: CC1(C)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
To a flask containing 4-(4-nitrophenoxy)quinolin-7-ol (14.45 g, 45.33 mmol) was added a solution of sodium hydroxide (3.63 g, 90.66 mmol) in water/95% EtOH (90 mL/10 mL) followed by isobutylene oxide (12.12 mL, 136 mmol, pre-cooled to 0° C.). After stirring at 45° C. for 10 minutes, more isobutylene oxide (12.12 mL, 136 mmol, pre-cooled to 0° C.) was added. The reaction was continued to stir for additional 12 hours. The mixture was cooled to room temperature and continued to stir for 4 hours, then cooled to 0° C. and stirred for additional 10 minutes. The resulted solid was filtered, and then dissolved in DCM (130 mL). The solution was filtered and concentrated in vacuo. The residue was washed with petroleum ether (30 mL), and dried in vacuo at 45° C. overnight to afford the title compound as a yellow solid (6.86 g, 42.7%).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[N:6][S:5][N:4]=1.[NH2:9][CH2:10][CH2:11][SH:12].[O-]CC.[Na+]>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:12][CH2:11][CH2:10][NH2:9])=[N:4][S:5][N:6]=1
Reactant: NCCS
Reactant: Clc1nsnc1CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCSCc1nsnc1Cl

Procedure:
2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethylamine may be prepared by the following route: 3-Methyl(1,2,5)thiadiazole is chlorinated for 4 days in acetonitrile at 25° to give 4-chloro-3-methyl(1,2,5)thiadiazole (oil) which is treated with N-bromosuccinimide in carbon tetrachloride to give 3-bromomethyl-4-chloro(1,2,5)thiadiazole (oil), the 100 MHz n.m.r. in CDCl3 had singlet at 4.66δ. 3-Bromomethyl-4-chloro(1,2,5 )thiadiazole was treated with cysteamine and sodium ethoxide in ethanol to give 2-(4-chloro-3(1,2,5)thiadiazolylmethylthio)ethylamine (oil). A 60 MHz n.m.r. spectrum (CDCl3) gave a singlet at 3.91 attributed to the Het-CH2 -S protons.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][O:12][C:13]([C:15]1[C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[C:16]2[C:17]([CH:9]=[O:10])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)cc12
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)c(C=O)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.42 g, 2.71 mmol) was added to DMF (0.99 g, 13.57 mmol) at 0° C. The resulting colorless solution was added dropwise to a solution of 2-(4-chloro-phenyl)-1H-indole-4-carboxylic acid methyl ester (0.52 g, 1.81 mmol) in 10 mL dry CH2Cl2 at 0° C. The reaction was stirred at 0° C. for 10 min then quenched by addition of 5 mL 2 M NaOAc(aq). The layers were separated and the aqueous layer extracted once with CH2Cl2. The combined organic layers were dried (MgSO4) then concentrated in vacuo leaving anorange oil which crystallized on standing. The crystals were rinsed with CH2Cl2 then dried in vacuo to yield 2-(4-chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl ester, 231 mg (41%) as an off-white solid: m.p. 221-222° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.93 (s, 3H), 7.49 (app t, J=7.5 Hz, 1H), 7.71 (m, 4H), 7.94 (d, J=7.8 Hz, 2H), 9.71 (s, 1H), 13.67 (br s, 1H). MS (electrospray, [M−H]) 312.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(OCc1nc(CCl)cs1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1csc(COC(=O)c2ccccc2)n1)OCC
Temperature: 150 °C
Reaction time: 17 h
Yield: 90.6 %

Procedure:
A mixture of (4-chloromethyl-1,3-thiazol-2-yl)methyl benzoate (6.4 g), triethyl phosphite (8.7 g) was stirred at 150° C. for 17 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v)-ethyl acetate to give {4-[(diethoxyphosphoryl)methyl]-1,3-thiazol-2-yl}methyl benzoate as a yellow oil (8.0 g, yield 91%).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([C:7]1([CH3:12])[O:11][CH2:10][CH2:9][O:8]1)[CH3:6])C.[OH-].[K+]>O1CCOCC1.O.O>[CH3:12][C:7]1([CH:5]([CH3:6])[C:4]([OH:13])=[O:3])[O:11][CH2:10][CH2:9][O:8]1
Reactant: CCOC(=O)C(C)C1(C)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)C1(C)OCCO1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-propionic acid ethyl ester of Example 1a (31 g, 0.1647 mol) was dissolved in the mixture of dioxane-water (1:1, 350 mL) containing potassium hydroxide (35.63 g, 0.63 mol). The reaction mixture was stirred overnight at 35° C. and concentrated under high vacuum to give a white solid which was dissolved in water (200 mL) and extracted with dichloromethane (100 mL×2). The aqueous portion was acidified to pH=2 with 2N aqueous hydrochloric acid and the product was extracted with chloroform. The organic layer was washed with brine (300 mL), dried with sodium sulfate and concentrated under vacuum. 2-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid was isolated as clear oil (20.34 g, 77%) which did not require further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:14]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (430 mg, 1.0165 mmol) and piperidine (173 mg, 2.0352 mmol) were dissolved in methylene chloride (30 ml), then 4-dimethylaminopyridine (62 mg, 0.5081 mmol) and WSC-HCl (487 mg, 2.5404 mmol) were added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (334 mg, 0.6816 mmol, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 500 mg, 1.6 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.7 ml, 4.0 mmol) followed by isonicotinoyl chloride hydrochloride (707.7 mg, 4.8 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}isonicotinamide (11, 392.5 mg) as white solids in 59% yield: 1H NMR (500 MHz, DMSO-d) δ 13.1 (s, 1 H), 8.81 (d, J=5.7 Hz, 2 H), 8.50 (s, 1 H), 8.41 (s, 1 H), 8.36 (s, 1H), 8.00 (d, J=5.7 Hz, 2 H), 7.41 (s, 2 H), 7.30 (s, 1 H), 2.13 (s, 6 H). ESI-MS: m/z 420.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1

Procedure:
A mixture of 3-(4-fluorophenyl)-5-methyl-l-(4-piperidyl)-1H-indole 3d (6.0 g). K2CO3 (3.0 g) and dichloromethane (50 ml) was cooled to 0°-5° C. and a solution of methyl chloroformate (2.2 g)in dichloromethane (50 ml) was added during 0.5 h. After reaction for further 2 h at room temperature the reaction mixture was washed with water (2×100 ml) and dried (MgSO4). Evaporation of the solvents in vacuo afforded the title compound, which was used without further purification. Yield: 6.7 g, (oil).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:27][CH2:28][CH3:29])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46](Cl)(=[O:48])=[O:47]>C1COCC1>[N:21]1([C:19]([N:16]2[CH2:15][CH2:14][CH:13]([N:12]([CH2:27][CH2:28][CH3:29])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([O:1][S:46]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[Cl:39])(=[O:48])=[O:47])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[O:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(O)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3ccccc3Cl)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of {4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (50 μmole in 420 μL DCM) was added 30 μL of DIEA followed by 220 μL of a 0.25M solution of 2-chlorobenzenesulfonyl chloride in THF. The solution was allowed to stir for 24 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 2-Chloro-benzenesulfonic acid 7-{[1-(morpholine4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester 40 (5.1 mg), [M+H]+=690.