Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:31])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][Br:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([O:29]C)[CH:12]=3)=[CH:4][CH:3]=1.Br.CC(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:31])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][Br:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:29])[CH:12]=3)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-(2-bromoethoxy)benzyl)-7-methoxychromen-2-one (16.5 grams, 33 mmol) and 150 mL of 30% HBr/HOAc in a sealed tube was warmed at 100° C. for 8 h. The reaction mixture was cooled to room temperature and poured into 300 mL of water. The resulting solid was collected by filtration and purified using flash chromatography to provide the desired product (12.5 g, 78%). 1H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 7.47 (d, 2H, J=8.5 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.33 (d, 2H, J=8.5 Hz), 7.05 (d, 2H, J=8.5 Hz), 6.83 (d, 2H, J=8.5 Hz), 6.75 (d, 1H, J=2.2 Hz), 6.70 (dd, 1H, J=8.8, 2.2 Hz), 4.24 (t, 2H, J=5.7 Hz), 3.94 (s, 2H), 3.76 (t, 2H, J=5.7 Hz). MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1)(=O)=O.C(O)(=O)C.[Sn].Cl>O>[SH:2][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(S)cc2c1OCCO2
Temperature: 90 °C
Yield: 89.7 %

Procedure:
243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and 654 cm3 of acetic acid were introduced into a balloon flask provided with an agitator and a condenser. The mixture was heated to 90° C. and then cooled to 45° C. 389 g of tin and 1,744 cm3 of hydrocloric acid were then added. The mixture was heated to 55°-60° C., cooled and poured into water. The precipitate was dried off, washed and dried. 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 191°-192° C.; yield: 90%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]([O:25]C)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=2)=[N:11][CH:10]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[C:3]([C:23]([OH:25])=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CO)cn3)s2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nccc(Sc2cnc(Nc3ccc(CO)cn3)s2)c1F
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Methyl 3-fluoro-4-(2-(5-(hydroxymethyl)pyridin-2-ylamino)thiazol-5-ylthio)picolinate (0.750 g, 1.91 mmol) was dissolved in THF (20 mL) and treated with NaOH (5N, 2.5 mL, 12.5 mmol) at 23° C. The reaction was stirred for 2 hours, then water was added. The reaction was acidified with conc. HCl to pH ˜2. The solvent was evaporated and the residue was diluted with water. This was extracted with ethyl acetate/THF (3×) and the combined organic layers were then dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (0.630 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 4.46 (2H, s), 5.22 (1H, s), 7.04-7.12 (2H, m), 7.74 (1H, dd, J=8.34, 2.27 Hz), 7.84 (1H, br s) 8.24 (1H, d, J=1.52 Hz), 8.31 (1H, d, J=5.05 Hz), 11.89 (1H, s), 13.75 (1H, s). LC/MS (M+H)+: 379. HPLC ret. time (Condition N): 2.463 min.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1.O>O1CCCC1>[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)c2c1CCCC2
Reactant: CC(C)(C)N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
Tert-butyl amine [8.5 g, 12.32 ml, 116.0 mmol) was added dropwise to a stirred suspension of 4-bromo-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride (59a, 12.0 g, 38.8 mmol) in 150 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at a temperature of about 25° C. for 2 hours. The progress of the reaction was monitored by TLC. Water (100 ml) was added to the reaction mixture, and the mixture so obtained was extracted with ethyl acetate (2×150 ml). The combined organic layer was then dried over sodium sulphate, and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (2.34 g, 17.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:10]=2)[CH2:6][O:7]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (56.5 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.5 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was filtered and rinsed with isopropanol and hexanes/EtOAc (7:3) to give the title compound (46.9 mg, 73%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[N:29]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:37]([C:34]4[CH:35]=[C:36]5[C:31]([CH:30]=[N:29][NH:28]5)=[CH:32][CH:33]=4)=[O:38])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc5cn[nH]c5c4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), 1H-indazole-6-carboxylic acid (40 mg, 0.245 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 25% acetonitrile/75% water (0.1% TFA V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-6-carboxamide (45 mg, 36%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.69 (s, 1H), 8.84 (s, 1H), 8.74 (d, 1H, J=6.3 Hz), 8.14 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.63-7.44 (m, 2H), 6.92 (d, 1H, J=9.0 Hz), 4.62-4.25 (m, 2H), 3.96-3.66 (m, 10H), 2.35-2.11 (m, 3H). LC-MS: 516.9 [M+H]+, tR=1.38 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.76 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][N:3]=1.[Br-].[CH:18]1([CH2:24][Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C:10]([NH:9][CH2:8][C:5]1[C:4]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:2]=[CH:7][CH:6]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Reactant: [Zn+]CC1CCCCC1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccnc1CC1CCCCC1
Temperature: 60 °C
Yield: 68 %

Procedure:
Dissolve 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60° C. overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:17][N:16]2[CH2:25][CH2:26][CH2:27][C:15]=12>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:14]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[C:15]2[CH2:27][CH2:26][CH2:25][N:16]2[N:17]=1
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: c1ccc(-c2nn3c(c2-c2ccc4[nH]ccc4c2)CCC3)nc1
Yield: 3.5 %

Procedure:
In a similar fashion to Example 1, react 1H-indole-5-boronic acid (Fluka; 150 mg, 0.95 mmol) with 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 4; 250 mg, 0.95 mmol) to provide the title compound (10 mg, 4%) as an off-white solid. MS ESI+ m/e 301 (M+1). 1H NMR (CDCl3) δ 8.67-8.58 (m, 1H), 7.61 (s, 1H), 7.52-7.45 (m, 1H), 7.39-7.29 (m, 2H), 7.21-7.16 (m, 1H), 7.14-7.04 (m, 2H), 6.52-6.48 (m, 1H), 4.31-4.21 (m, 2H), 3.06-2.98 (m, 2H), 2.73-2.60 (m, 2H). TLC (SiO2): Rf 0.4 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:51]2([CH2:56][CH2:55][CH:54]([OH:57])[CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1>>[Cl:17][C:18]1[C:19]([O:57][CH:54]2[CH2:53][CH2:52][C:51]3([CH2:47][CH2:48][CH2:49][CH2:50]3)[CH2:56][CH2:55]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1CCC2(CCCC2)CC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2CCC3(CCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[4.5]decan-8-ol, the title compound was obtained as a colorless solid (0.06 g, 14%). 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.31 (d, J=12.6 Hz, 1H), 4.68-4.61 (m, 1H), 2.87 (s, 6H), 1.88-1.77 (m, 2H), 1.65-1.51 (m, 8H), 1.44-1.32 (m, 6H); MS (ES−) m/z 431.2, 433.2 (M−1).
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CCCCCCCCC.C(Cl)(=O)C1C=CC=CC=1.C(Cl)(=O)CCCCCCCCCCCCCCC.C(=O)(O)[O-].[Na+]>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Product: Nc1nc2c(ncn2[C@@]2(C(=O)c3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 0 °C

Procedure:
This compound was prepared using the procedure for palmitoyl-2′-deoxyguanosine, substituting the appropriate amount of benzoyl chloride for palmitoyl chloride, and substituting a 1:1 mixture of ice water and saturated aqueous sodium bicarbonate solution in the workup.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:19]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCOC(C)=O.CO>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 2.75 h
Yield: 99.2 %

Procedure:
To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl)ethane-1,2-dione (250 mg, 0.54 mmol) in EtOAc (6 mL) and MeOH (2 mL) at 0° C. was added NaBH4 (20 mg, 0.54 mmol). After 2.75 hours at 0° C., more NaBH4 (20 mg, 0.54 mmol) was added. After 1.25 hours at 0° C., the reaction was quenched with HOAc (few drops) and H2O (2 mL). The pH was adjusted to 5 (by pH paper) with HOAc and partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layers were dried over Na2SO4 and concentrated to provide 0.25 g (99%) of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)1H-pyrrol-3-yl]-2-hydroxy-ethanone as a crisp foam. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=7.4 Hz), 7.48-7.19 (m, 10H), 7.14 (t, 1H, J=2.0 Hz), 7.06 (t, 1H, J=2.6 Hz), 6.31 (t, 1H, J=2.4Hz), 5.11 (d, 1H, J=7.4 Hz), 4.29 (d, 1H, J=6.6 Hz), 3.99-3.95 (m, 1H), 3.76 (d, 1H, J=9.2 Hz), 3.60 (dd, 1H, J=5.0, 8.6 Hz), 3.08-3.02 (m, 1H), 2.90 (dd, 1H, J=10.5, 13.4 Hz), 1.82 (s, 3H), 1.60 (s, 3H). Anal. Calculated for C30H30N2O3•0.4 H2O: C, 76.05; H, 6.55; N, 5.91. Found: C, 76.17; H, 6.66; N, 5.74.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][CH:6]([CH3:10])[C:7](Cl)=[O:8]>C(OCC)C>[OH:3][CH2:2][CH2:1][O:4][C:7](=[O:8])[CH:6]([Cl:5])[CH3:10]
Reactant: CC(Cl)C(=O)Cl
Reactant: OCCO
Solvent: CCOCC
Product: CC(Cl)C(=O)OCCO
Temperature: 65 °C
Yield: 71.7 %

Procedure:
The compound depicted in FIG. 1E (hereinafter "Compound 1E" was made as follows: ethylene glycol (310.0 g, 5.00 moles) was heated to 60° C. before beginning the dropwise addition of 2-chloropropanoyl chloride (127.0 g, 1.00 mole) dissolved in 300 ml of anhydrous diethyl ether. The reaction was exothermic and the temperature rose to 65° C. The ether was allowed to boil off throughout the reaction. The reaction was heated to maintain 65° C. throughout the latter part of the addition and for 30 minutes after completion. The reaction solution was separated into two 250 ml batches that were added separately to 400 ml of H2O and extracted three times with 200 ml of hexane. The hexane extract was discarded and the aqueous phase was saturated with potassium chloride and extracted three times with 200 ml of ethyl acetate. The ethyl acetate was evaporated in vacuo and the concentrate was diluted with 300 ml of diethyl ether and dried over a mixture of anhydrous potassium carbonate and magnesium sulfate. After removing the solvent, the oil was vacuum distilled to give 109.4 g (71.0% yield) of approximately 95% pure 2-hydroxyethyl-2-chloropropanoate. The colorless, clear liquid had a boiling point of 85°-87° C./0.20 mm Hg. The structure of the compound was in agreement with the following data:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][CH:16]=1)=[O:14]>CO>[NH2:1][C:2]1[N:6]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:17][CH:16]=2)=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCN(CC)c1ccc(C(=O)CBr)cc1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CO
Product: CCN(CC)c1ccc(C(=O)Cn2c(N)nc3ccccc32)cc1
Yield: 36.4 %

Procedure:
A solution of 2-aminobenzimidazole (197 mg, 1.5 mmol) and 2-Bromo-4′-(diethylamino)acetophenone (402 mg, 1.5 mmol) in MeOH (7 mL) was stirred at r.t. for 18 hours. The volatiles were removed in vacuo and NaHCO3 (sat. aq., 30 mL) was added. The aqueous mixture was extracted with EtOAc (3×30 mL). The combined EtOAc extracts were dried with MgSO4 and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient up to 5:95 (MeOH:DCM) to isolate 2-(2-amino-1H-benzo[d]imidazol-1-yl)-1-(4-(diethylamino)phenyl)ethanone (176 mg, 36%) as a beige solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(=[O:5])=[O:4].[S-:20][C:21]#[N:22].[K+].BrBr.[ClH:26]>C(O)(=O)C.C(O)C>[ClH:26].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:14]=2[S:20][C:21]1=[NH:22])(=[O:4])=[O:5]
Reactant: N#C[S-]
Reactant: CNS(=O)(=O)CCNc1ccc(OC(F)(F)F)cc1
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNS(=O)(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21

Procedure:
The procedure is as in Example 3, starting with N-methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (3.5 g), potassium thiocyanate (4.7 g) and bromine (2.2 g) in acetic acid (30 cc). After 18 hours at a temperature in the region of 20° C., neutralization with 30% strength sodium hydroxide and extraction with ethyl acetate, a crude product is obtained, which product is converted to a hydrochloride by adding 4.2N ethereal hydrogen chloride (3 cc) in ethanol (25 cc) and recrystallized in absolute ethanol (50 cc). The N-methyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulphonamide hydrochloride thereby obtained (2.1 g) melts at 242° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[CH:9]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([S:29]([CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])(=[O:31])=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:43]([C:42]2[CH:41]=[CH:40][C:39]([C:35]3[O:36][C:37]([CH3:38])=[C:33]([CH2:32][S:29]([CH:26]4[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]4)(=[O:30])=[O:31])[N:34]=3)=[CH:47][CH:46]=2)=[O:44])[CH:9]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Triethylamine (440 mg, 4.36 mmol, 3.00 equiv) was added dropwise with stirring to a solution of pyridin-3-ylmethanamine (170 mg, 1.57 mmol, 1.10 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (670 mg, 1.44 mmol, 1.00 equiv), EDCI (330 mg, 1.73 mmol, 1.20 equiv) and HOBT (230 mg, 1.70 mmol, 1.20 equiv) in N,N-dimethylformamide (10 mL) contained in a 50-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration and dried in an oven under reduced pressure to give 0.74 g (93%) of tert-butyl 4-((2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 555 [M+H]+, 455.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[Na].Br[CH2:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14]>>[CH:15]1([C:13](=[O:14])[CH2:12][O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)[CH2:17][CH2:16]1
Reactant: O=C(CBr)C1CC1
Reactant: CC1(C)OCC(CO)O1
Agent: [Na]
Product: CC1(C)OCC(COCC(=O)C2CC2)O1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Charge a flask with (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10 g, 75.7 mmol), heat to 85° C. and add freshly cut sodium (465 mg, 20.23 mmol) Heat to 85° C. and stir for 1 hour. Add 2-bromo-1-cyclopropylethanone (3.0 g, 18.4 mmol) maintain the temperature at 85° C. and stir for 30 minutes. Filter and wash the solid with ACN (20 mL). Collect the filtrate and concentrate under reduced pressure. Purify via HPLC conditions Z to give the title compound as a colorless oil. (650 mg, 16.5%). MS (m/z): 215 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH:3]=[O:4].BrBr.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:5])[CH:3]=[O:4]
Reactant: CC(C)C=O
Reactant: C1CCNC1
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylpropanal (5.6 mL, 61.8 mmol) in DCM (75 mL) cooled with an ice bath was added bromine (3.2 mL, 61.8 mmol) dropwise. After 1 hr, the solution was evaporated, stirred in DCM (8 ml) at room temperature and pyrrolidine (0.94 mL, 11.26 mmol) was added. After stirring 4 h, the mixture was diluted with brine and the layers separated. The organic layer was washed with 1M HCl and then the aqueous layer was basified with KOH to pH=10-11. This was then extracted with DCM and the organic layers were combined, dried (MgSO4), filtered and concentrated to isolate 2-methyl-2-pyrrolidin-1-yl-propanal oil as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([CH:15]2[CH2:17][CH2:16]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:25].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([NH2:25])[CH:15]2[CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C(C1CC1)C1CCN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC(C1CC1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1 g sample of the compound from step 470b, 3.37 g of ammonium acetate and 274 mg of NaBH3CN were dissolved in 15 mL of methanol, 1.2 g of 4 Å molecular sieves were added, and the mixture was stirred at room temperature under N2 for 16 hours. The mixture was filtered, the sieves washed with methanol, the wash and filtrate combined, and concentrated. The residue was dissolved in 100 mL of methylene chloride, and 30 mL of 15% NaOH was added. The organic phase and a second wash of the aqueous phase were combined and washed with water and brine, then dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel to give 460 mg of the title compound.