Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:27]=[C:26]2B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.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>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:27]=[C:26]2[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2cc(Br)ccc21
Reactant: COc1ccc(COc2cc(Cl)nc(S(C)(=O)=O)n2)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(COc2cc(-c3cn(C(=O)OC(C)(C)C)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 41.4 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidine (600 mg, 1.825 mmol) and tert-butyl 5-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (770 mg, 1.825 mmol) in p-dioxane/H2O (4:1, 6 mL) followed by Pd(PPh3)4 (105 mg, 0.091 mmol) and potassium carbonate (220 μL, 3.65 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-25% EtOAc in Hexanes) to give tert-butyl 5-bromo-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole-1-carboxylate (445 mg, 0.756 mmol, 41.4% yield) as a half solid. MS (ESI, pos. ion) m/z: 587.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:35]([CH3:37])[CH3:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:44]([C:48]1[CH:49]=[C:50]([NH2:55])[C:51]([NH2:54])=[CH:52][CH:53]=1)([CH3:47])([CH3:46])[CH3:45].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH3:6].[NH2:55][C:50]1[CH:49]=[C:48]([C:44]([CH3:47])([CH3:45])[CH3:46])[CH:53]=[CH:52][C:51]=1[NH:54][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:26][C@@H:18]1[C@@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]4[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=4[O:2][CH3:1])[C:8]=3[CH:15]=[CH:14]2)[O:17]1)[CH:35]([CH3:36])[CH3:37]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)O)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)Nc3ccc(C(C)(C)C)cc3N)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Product: N
Temperature: 25 °C
Reaction time: 19 h
Yield: 2 %
Yield: 171.9 %

Procedure:
A solution of 5-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)pentanoic acid (131 mg, 0.219 mmol) and 4-tert-butylbenzene-1,2-diamine (40 mg, 0.24 mmol) in N,N-dimethylformamide (2.2 mL) was treated with N,N-diisopropylethylamine (84 uL, 0.48 mmol) dropwise followed by PyBop reagent (120 mg, 0.24 mmol). The solution was allowed to stir at room temperature for 19 h, whereupon HPLC indicated the reaction was complete. The reaction mixture was concentrated under high vacuum. The residue was taken up in 40 mL CH2Cl2 and washed with 20 mL portions of H2O, 5% citric acid, and brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield a tan viscous glass. The crude material was purified by flash chromatography (40 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2 to yield the title compound (140 mg, 86%) was a slightly tan glass: MS (ESI+) for C41H57N7O6 m/z 744.9 (M+H)+; HPLC purity (combined for the two regioisomers) 91% (ret. times, 3.25 and 3.28 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[NH:30][CH2:31][C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:30]([C:23]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cc1cc(C)c(NCc2nnn(C)n2)c(C)c1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2c(C)cc(C)cc2C)[C@H]1O
Yield: 35 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (400 mg, 1.43 mmol) obtained in step 1 of example 2 and N-(2,4,6-trimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (260 mg, yield: 35%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:11][OH:12].C[O-].[Na+]>CO>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:11][OH:12])[NH2:5]
Reactant: N#Cc1ccccc1O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccccc1O

Procedure:
2-Hydroxybenzonitrile (10 grams), hydroxylamine HCl (7 g.) in 150 ml. methanol, and sodium methoxide (9.0 grams) were refluxed for about 18 hours. The reaction mixture was then filtered and the ethanol evaporated. Next water was added and the product extracted into ethyl acetate. Drying and evaporation of the solvent left an oily product which solidified upon standing. The identity of the final product was confirmed by NMR and IR analysis.
Reaction SMILES: [C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O:17][C:18]([CH2:20]Cl)=[O:19].C1[O:24]C1.ClC(Cl)C>>[C:1]1([P:7]([CH2:20][C:18]([OH:17])=[O:19])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCl
Reactant: C1CO1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: O=C(O)CP(=O)(c1ccccc1)c1ccccc1
Temperature: -5 °C

Procedure:
Into a 0.15 l four-neck flask provided with a thermometer, stirrer, gas-supply pipe and a cooler there are charged 33.07 g (0.15 mole) of diphenylchlorophosphine and 18.37 g (0.15 mole) of ethyl ester of chloroacetic acid. The flask contents are purged with nitrogen and cooled to the temperature of -5° C. Thereafter, a mixture of ethylene oxide and nitrogen in the ratio of 1:1 is bubbled into the solution at a temperature of the reaction mixture of from -5° to +5° C. After addition of 6.6 g (0.15 mole) of ethylene oxide and completion of the reaction, the temperature is slowly elevated to 140° C. simultaneously distilling-off dichloroethane. In doing so, ethyl ester of diphenylphosphinylacetic acid is formed.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](O)[CH2:3][CH2:2]1.[N+:8]([C:11]1[CH:12]=[N:13][NH:14][CH:15]=1)([O-:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N+:8]([C:11]1[CH:12]=[N:13][N:14]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:15]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a stirred solution of tetrahydro-2H-pyran-4-ol (1 equiv), 4-nitro-1H-pyrazole (1 equiv) and triphenylphosphine (1.2 equiv) in THF (1.0 M) was added diisopropyl azodicarboxylate (1.5 equiv) in THF (2.0 M) at 0° C. The mixture was stirred at room temperature overnight. The crude product was purified by silica gel chromatography (2.5% MeOH in DCM) to afford the desired product (23% yield) as a white solid. MS (ESI) m/z 198.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24]Cl)[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:70].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24][I:70])[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
The compound obtained in (A) was dissolved in 200 ml of acetone, and 3.38 g (22.5 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 600 ml of ethyl acetate and 200 ml of a 10% sodium thiosulfate aqueous solution were added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by slica gel flush column chromatography (ethyl acetate/n-hexane=1/2), and concentrated under reduced pressure. Then, diisopropyl ether was added thereto, and 7.0 g (yield: 63.0%) of a powder of the above-identified compound was collected by filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: COc1ncc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-methoxy-pyrimidine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][CH:14]([C:28]([OH:30])=[O:29])[C:15]1[CH:16]=[CH:17][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:19]([F:21])[CH:20]=1.[ClH:31].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][CH:14]([C:28]([OH:30])=[O:29])[C:15]1[CH:16]=[CH:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:19]([F:21])[CH:20]=1.[ClH:31]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(N)O
Temperature: 25 °C

Procedure:
In 1 ml of dichloromethane, 720 mg (1.79 mmol) of the Boc-aminopropanol-flurbiprofen obtained above was dissolved, and 4 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring under ice-cooling for 3 minutes and at room temperature for 3 hours and 10 minutes. After confirming disappearance of Boc-aminopropanol-flurbiprofen by TLC, diethyl ether was added thereto, followed by decantation twice. Thereafter, the residue was dried under reduced pressure to give the titled substance at a yield of 352 mg (94%). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[C:12]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[CH2:9][CH3:10].[O-:26][C:27]#[N:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:8]([N:11]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[C:12]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27]([NH2:28])=[O:26])[CH:20]=1)[CH2:9][CH3:10]
Reactant: N#C[O-]
Reactant: CCCn1c(CC)ccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCCn1c(CC)ccc1Cc1cccc(NC(N)=O)c1
Yield: 74.5 %

Procedure:
A solution of 3.5 ml (39 mmol) of trifluoroacetic acid in 200 ml of methylene chloride was added dropwise, over a 2 hour period and under nitrogen atmosphere, to a stirred suspension of 4.8 g (19 mmol) of 1-propyl-2-(3'-aminobenzyl)-5-ethylpyrrole and 2.58 g (39 mmol) of sodium cyanate in 400 ml of anhydrous methylene chloride and 90 ml of methanol. The reaction mixture was stirred at room temperature for 18 additional hours, 2 g (18 mmol) of sodium carbonate were added and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using hexane-acetone (1:1) as eluant, obtaining 4.04 g (72%) of the title compound, 1-propyl-2-(3'-ureidobenzyl)-5-ethylpyrrole, which was recrystallized from ether-hexane. M.P. 116°-118° C.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](C4C=C5C(C=NN5C)=CC=4)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11].[C:51](#[N:53])[CH3:52]>>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:18]4[CH:15]=[C:52]5[C:21](=[CH:20][CH:19]=4)[N:22]([CH3:23])[N:53]=[CH:51]5)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=1)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: CC#N
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.6 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethanol (25 mg, 0.049 mmol) in ACN (3 mL) at room temperature and stirred for one hour. The reaction mixture was quenched with saturated Na2SO3 solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (H2O/ACN+0.1% TFA) to give the desired product after lyophilization. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); found: 597.2, 599.2. 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J=5.3 Hz, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.14-8.08 (m, 2H), 7.94-7.87 (m, 2H), 7.73-7.63 (m, 2H), 7.61-7.54 (m, 3H), 5.26 (s, 1H), 4.10 (s, 3H), 2.63 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:26])=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][CH2:23][C@@H:9]2[CH2:10][C@@H:11]([S:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][NH:8]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)c3ccc(F)cc3)N(C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2CN[C@H](CCC(=O)c3ccc(F)cc3)C2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.539 g (1.14 mmol) (2R,4R)-2-[3-(4-Fluoro-phenyl)-3-oxo-propyl]4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 10 ml CH2Cl2 was treated at 0° C. with 0.43 ml TFA. After 30 min the reaction was warmed up to room temperature (2 h) and evaporated to give (2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-one; compound with trifluoro-acetic acid, MS: 374 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]=C)=[N:16][C:15]=23)[CH:2]=1.N1C(C)=CC=CC=1C.O.[O-:48]S([O-])(=S)=O.[Na+].[Na+]>O1CCOCC1.O=[Os](=O)(=O)=O>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]1[N:14]2[N:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[C:15]2[N:16]=[C:17]([CH:37]=[O:48])[CH:18]=1
Reactant: O=S([O-])([O-])=S
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (Int-8a, 0.7 g, 1.3 mmol) in 1,4-dioxane (10 mL) was added 2.5 wt % OsO4 in 1,4-dioxane (1.0 g, 0.02 mmol), 2,6-lutidine (0.6 mL, 5.2 mmol) and H2O (2 mL), and the resulting mixture was stirred at room temperature for 20 minutes. NaIO4 (0.8 g, 3.81 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. L C/MS analysis at that time showed the diol intermediate was still present. Therefore, more NaIO4 (0.3 g, 1.3 mmol) was added, and the reaction mixture was stirred for 12 hours for full conversion to the product. Saturated Na2S2O3 solution (10 mL) was added and the mixture was stirred for 10 minutes. The organics were then extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (Int-8b) as a yellow solid (0.6 g, 1.2 mmol, 92%). LCMS: 2.67 mins, m/z=550.0 (MH+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:20])[C:5](=[O:19])[S:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:17]=[O:18])=[N:14]2)=[CH:9][CH:8]=1>C(O)C.C(Cl)(Cl)Cl>[CH3:3][N:4]([CH3:20])[C:5](=[O:19])[S:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH2:17][OH:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)Sc1ccc2ccc(C=O)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C(=O)Sc1ccc2ccc(CO)nc2c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
Referring now to FIG. 22, NaBH4 (6.2 mg, 0.165 mmol) was added to a solution of 18 (43.1 mg, 0.165 mmol) in ethanol (1 mL), and the resulting mixture was stirred at room temperature. After TLC indicated the reaction was complete, the solvent was evaporated and the residue obtained was dissolved in chloroform. The solution was then washed with brine (×2), dried over Na2SO4, and evaporated to provide 19 (36.5 mg, 0.139 mmol, 85% yield) was obtained and carried to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:32])[CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH3:32][N+:25]([CH:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)([CH3:33])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])/[CH:14]=[CH:13]/[C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:19][CH:20]=1
Reactant: CI
Reactant: Cc1ccc(-c2ccc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)s2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(/C=C/C(=O)Nc3ccc(C[N+](C)(C)C4CCOCC4)cc3)s2)cc1
Product: [I-]
Reaction time: 48 h

Procedure:
To a solution of (E)-3-[5-(4-methylphenyl)thiophen-2-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]acrylamide (100 mg) in DMF (3 ml) was added at room temperature methyl iodide (0.5 ml), and the mixture was stirred for 2 days. Under reduced pressure, the mixture was concentrated, and to the residue was added acetonitrile. The resulting crystals were collected by filtration to give yellow crystals of N,N-dimethyl-N-[4-[[(E)-3-[5-(4-methylphenyl)thiophen-2-yl]-2-propenoyl]amino]benzyl]-4-tetrahydropyranyl ammonium iodide (Compound 279) (101.1 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: O=C=Nc1ccccc1F
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3ccccc3F)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (670 mg, 3.6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 2-fluoro-1-isocyanato-benzene (189 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-fluoro-phenyl)-acetamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([CH:16]3[CH2:17][CH2:18][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
8-Chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (product from Example 233A) (4.18 g, 13 mmol) was dissolved in toluene (175mL). Ethyl chloroformate(11.6 g, 110 mmol, 10.2 mL) was then added and the reaction mixture was heated to ~120° C. overnight. All volatiles were stripped off and the crude product was purified on silica gel column eluting with 50% EtOAc- hexanes to give the title compound as a white solid(MH+ 385).