Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([O:21]C)[N:15]=1)[CH3:10].[Na+].[Cl-]>CS(C)=O.C(N(CC)CC)C>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[NH:15][C:16](=[O:21])[CH:17]=[C:18]([N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][F:1])[CH2:4]2)[N:19]=1)[CH3:10]
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Reactant: FCC1CNCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Temperature: 85 °C
Yield: 50.4 %

Procedure:
In a 50 ml round-bottomed flask, 680 mg of 2-fluoromethylmorpholine (Yoshikazu Jinho et al.; J. Med. Chem., 37(17), 2791-2796; 1994) and 0.63 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester (example 8b, step 2b) are placed in 15 ml of DMSO and 1,013 ml of triethylamine. The reaction medium is heated for 18 h at 85° C. The reaction medium is poured into a saturated NaCl solution and the mixture is extracted with 3 times 25 ml of ethyl acetate. The organic extracts are combined and washed with a saturated NaCl solution, dried over magnesium sulfate and evaporated. The compound obtained is chromatographed on silica gel (15-40 μm, Merck), elution being carried out with a gradient of dichloromethane and methanol (98/2 to 95/5 v/v). The fractions containing the expected compound are combined and evaporated, so as to give (±)-[4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid ethyl ester (412 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:1]=[CH:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccncc1
Reactant: NCc1ccncc1
Solvent: CO
Product: C(=NCc1ccncc1)c1ccncc1
Reaction time: 0.01 h

Procedure:
In this Example, reductive amination of 4-pyridine-carboxaldehyde (2) with 4-(aminomethyl)pyridine (1) was carried out using a one-pot two-step protocol to produce bis((pyridin-4-yl)methyl)amine (4). Time-resolved mass spectra of the aldehyde-amine condensation step and the imine reduction step are shown in FIG. 16. Ions were identified according to their m/z values and confirmed by tandem mass experiment. Reactant 1 was first injected into the methanol reaction solvent. Ions of protonated 1 at m/z 109 were detected at 0.4 min later, on the heels of which the protonated dimer at m/z 217 appeared and reached its steady state within 4.8 s. (FIG. 16 panels A-B) After reactant 2 was injected into the reaction solution and the protonated methanol adduct ions of the monomer and dimer of 2 at m/z 140 and 279 showed up. The ions of the intermediate (pyridin-4-yl)-N-((pyridin-4-yl)methylene)methanamine (3) at m/z 198 and 230 formed quickly and the intensity increased sharply (FIG. 16 panel C). The intensity of ions of 1 decreased but the ions did not disappear, which corresponded to the fact that this is an equilibrium reaction (FIG. 16 panel D). About 50 min later, sodium borohydride solution was injected into the system. The sodiated adduct ions of product 4 at m/z 222 started to appear, while the intermediate ions of 3 decreased a lot (FIG. 16 panel E). Ten minutes later, the peak of the product 4 was reaching its highest intensity (FIG. 16 panel F). The selected ion chronogram shows dynamic changing of ions corresponding to the precursor 1, intermediate 3 and product 4 (FIG. 17). The kinetic process of reductive amination can be clearly seen. The first condensation step of this reaction happened very fast; once 2 was added to the solution of 1, it took less than 1 min for the reaction to reach equilibrium. The intermediate 3 was generated simultaneously with the decrease of 1. The second reduction step was not as fast as the first step. With the reduction of intermediate 3, the first step was driven to the right. Thus ions of 1 were depleted. Altogether, it took around 10 min for the product 4 to reach its highest intensity. The total monitoring time was 90 min without any clogging in the fused-silica capillary using high concentrations of reaction solution that are representative of those of industrial interest.
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Cl:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.2 using 6-chloro-5-iodonicotinic acid and 4-(chlorodifluoromethoxy)aniline to afford an off-white powder. HPLC (Condition 4) tR=6.47 min, UPLC-MS (Condition 3) tR=1.26 min, m/z=456.8 [M−H]−.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:36])[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39](I)[CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:36])[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH2:39][CH3:40])[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cn[nH]c4)[C@@H](Cc4ccccc4)C3)ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cnn(CC)c4)[C@@H](Cc4ccccc4)C3)ccc12
Temperature: 60 °C
Yield: 44.8 %

Procedure:
A solution of (S)-1-(2-benzyl-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)piperazin-1-yl)-2-(1H-pyrazol-4-yl)ethanone (101 mg, 0.21 mmol) in DMF (1 mL) was treated with sodium hydride (10 mg, 0.25 mmol) as a 60% dispersion in mineral oil. Once bubbling subsided, ethyl iodide (18 μL, 0.23 mmol) was added and the mixture was heated to 60° C. for 24 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (5 mL) followed by brine (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude residue was purified by silica gel chromatography eluting with a 0-10% MeOH in CH2Cl2 gradient to afford product as a colorless solid (48 mg, 44%). LC/MS 4.03 min, [M+1]+ 511.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([CH:21]=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[C-]#N.[K+].[CH3:26][OH:27]>O=[Mn]=O>[Cl:1][C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[C:10]([CH3:20])=[C:9]([C:21]([O:27][CH3:26])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)c2c(n1)c(C=O)c(C)n2COCC[Si](C)(C)C
Reactant: CO
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12

Procedure:
To a well stirred mixture of 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde from example A10 (9.49 g; 27.90 mmol), MeOH (50 mL), KCN (6.00 g; 92.10 mmol) and MnO2 (35.60 g, 383.30 mmol) acetic acid (1.68 g; 27.90 mmol) is added at ambient temperature. After 4 hours the dark mixture is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane:ethylacetate/9:1) affording the title compound as an pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][O:18][C:19]([C:21]1[CH:26]=[N:25][C:24](Cl)=[CH:23][N:22]=1)=[O:20].C(N(CC)CC)C>O1CCOCC1>[CH3:17][O:18][C:19]([C:21]1[N:22]=[CH:23][C:24]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=3[CH3:9])[CH2:11][C@H:12]2[CH3:16])=[N:25][CH:26]=1)=[O:20]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)cn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
3-Chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (1.20 g, 4.88 mmol), 5-chloro-pyrazine-2-carboxylic acid methyl ester (946 mg, 5.37 mmol), triethylamine (3.40 mL, 24.4 mmol), and 1,4-dioxane (10 mL) are combined in a 100 mL round-bottom flask fitted with a reflux condenser and heated to 80° C. for 24 h. The reaction is then allowed to cool to room temperature and stirred for 48 h. A beige solid precipitates during this time which is isolated by filtration, rinsing with H2O. The precipitate is dried in vacuo to afford the title compound (1.30 g, 71%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13]S(=O)(=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:17]1CCC(O)CC1>>[Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][O:17][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCC(Oc2ncccc2Br)CC1
Reactant: OC1CCOCC1
Product: Brc1cccnc1OC1CCOCC1

Procedure:
The title compound was prepared in a manner similar to that described in Step A for the synthesis of 4-((3-bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide using tetrahydro-2H-pyran-4-ol. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J=4.8, 1.7, 1H), 7.99 (dd, J=7.7, 1.7, 1H), 6.90 (dd, J=7.7, 4.8, 1H), 5.22 (m, 1H), 3.86-3.77 (m, 2H), 3.49 (m, 2H), 1.95 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(NC2CCCCC2)c(Br)c1
Yield: 98.1 %

Procedure:
A mixture of Example 86a (0.136 g, 0.5 mmol) and cyclohexanamine (0.198 g, 2.0 mmol) in dioxane (2 mL) was heated under microwave conditions (140° C., 1 hour). The solvent was removed, and the residue was purified by flash chromatography (3:2 ethyl acetate/hexanes) on silica gel to give 0.164 g of the title product.
Reaction SMILES: [NH:1]1[C:64](=[O:65])[C@H:60]([CH:61]([CH3:63])[CH3:62])[N:59]([CH3:66])[C:57](=[O:58])[C@@H:49]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:48][C:46](=[O:47])[C@H:34]([CH2:35][C:36](=[O:45])[O:37]CC2C=CC=CC=2)[NH:33][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].[H][H]>C1COCC1.[Pd]>[NH:1]1[C:64](=[O:65])[C@H:60]([CH:61]([CH3:63])[CH3:62])[N:59]([CH3:66])[C:57](=[O:58])[C@@H:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:48][C:46](=[O:47])[C@H:34]([CH2:35][C:36](=[O:37])[OH:45])[NH:33][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:20])[CH3:21])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: [H][H]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)OCc3ccccc3)NC(=O)CNC2=O)c(C)c2c1OC(C)(C)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)O)NC(=O)CNC2=O)c(C)c2c1OC(C)(C)C2
Yield: 83 %

Procedure:
A solution of 2 g of cyclo(Arg(Pbf)-Gly-Asp(OBzl)-DPhe-NMeVal) in 26 ml of THF is mixed with 0.5 g of Pd/C (10%). Hydrogen is passed through for 2 hours, the mixture is freed of the catalyst and the solvent is removed in vacuo. The product crystallizes after addition of 32 ml of acetone, and is filtered off and dried. Cyclo(Arg(Pbf)-Gly-Asp-DPhe-NMeVal) is obtained in a yield of 83%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([NH2:30])=O)[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:28]([C:26]1[N:27]=[C:23]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:31]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:22]=[CH:21][CH:20]=2)[O:24][CH:25]=1)#[N:30]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(N)=O)co3)c1)C2=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C#N)co3)c1)C2=O
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
(S)-2-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxamide (211 mg, 0.483 mmol) obtained in Step 1 was dissolved in pyridine (3 mL), and the mixture was stirred at 90° C. for 3.5 hours after adding p-toluenesulfonyl chloride (395 mg, 2.07 mmol). The mixture was diluted by addition of chloroform, and washed with 1 mol/L hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(4-cyano-1,3-oxazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (155 mg, 77%).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[CH2:19]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][C:16]([CH:30]=[O:31])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CN(C)C=O
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)cc1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
In a stream of argon, in tetrahydrofuran was dissolved 3.0 g (0.97 mmol) of dibutyl[4-[2-(thiophene-2-yl)vinyl]phenyl]amine. To this mixture, 9.0 ml of n-butyllithium (1.6 M solution in hexane) (14.4 mmol) was added dropwise under cooling. After the mixture was stirred for 1 hour, 0.87 g (11.9 mmol) of N,N-dimethylformamide was added dropwise thereto. After 20 minutes, the temperature was allowed to rise and 30 ml of water was added dropwise. Tetrahydrofuran was evaporated off. Extraction with chloroform, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 3.12 g of a reddish orange oily matter (yield: 95.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].O.P([O-])(O)(O)=[O:30].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[C:5]([OH:30])=[O:6]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 72 h

Procedure:
To a slurry of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (3.80 g, 10.1 mmol) and sodium dihydrogenphosphate hydrate (7.00 g, 50.7 mmol) in 40 mL 1:1 water/t-BuOH under nitrogen was added 2-methylbut-2-ene (37.6 mL, 355 mmol) and sodium chlorite (4.59 g, 50.7 mmol). The reaction mixture was allowed to stir rapidly for 3 days. The thick reaction mixture was concentrated in vacuo to remove the 2-methyl-2-butene, and the slurry diluted with water and filtered, rinsing water and MeOH. The resulting solid was dried in vacuo to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid as an off-white solid which was used without further purification. MS (ESI) m/z: Calculated: 390.1; Observed: 391.1 (M++1).
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[C:20]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: OBO
Product: O=Cc1cccnc1-c1cccc(OC(F)(F)F)c1

Procedure:
2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure with 2-bromonicotinaldehyde and (3-(trifluoromethoxy)phenyl)boronic acid (101 mg, 144 mg theoretical, 70.1%). LC-MS m/z 268 (M+1).
Reaction SMILES: C(OC1N=NC(C#CC2C=CC=CC=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](Cl)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:54]([C:56]1[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=1)#[CH:55]>>[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42]([C:55]#[C:54][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C#Cc1cc(F)cc(F)c1
Agent: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Product: Fc1cc(F)cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3,5-difluorobenzene.
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.CCOC(C)=O.[H][H]>CO.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:18]=1
Reactant: [H][H]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Nc1cc(N)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Yield: 81.9 %

Procedure:
To a stirred solution of ethyl 2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-nitrophenylcarbamate (0.15 g, 0.34 mmol) in 10 mL of MeOH: EtOAc was added Pd/C (10 wt. % on activated carbon, 50 mg), followed by charging with hydrogen under 50 psi for 2 hour. The crude was filtered through celite, concentrated, the residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound ethyl 5-amino-2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate as light yellow solid (114 mg). MS calcd for (C16H17BFN3O6S): 409.1. MS found (ESI negative): (M−H)−=408.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 9.30 (s, 1H), 8.49 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.24 (m, 2H), 7.20 (d, J=10 Hz, 1H), 6.18 (dd, J=8.8, 2 Hz, 1H), 6.09 (bs, 2H), 4.89 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2([CH3:13])[CH3:12].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][C:7]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CNc2c(F)cccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
A mixture of 7-fluoro-3,3-dimethyloxindole (EXAMPLE 99, step 5, 2.24 g 12.5 mmol) in toluene (15 mL) under nitrogen was heated at 80° C. Vitride (65 wt % in toluene, 6 mL, 19.3 mmol) was added dropwise via an addition funnel. The resulting solution was stirred at 80° C. for an additional 1.5 hours, then cooled in an ice bath. Aqueous sodium hydroxide solution (1N, 15 mL) was added slowly to quench the reaction. Water (15 mL) was added and the reaction mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (anhydrous sodium sulfate), filtered through a pad of silica gel, and concentrated under reduced pressure to yield 1.68 g (82%) of 7-fluoro-3,3-dimethylindoline as a colorless oil. MS (ES) m/z 166.1 ([M+H]+); HRMS: calcd for C10H12FN+H+, 166.1032; found (ESI, [M+H]+), 166.1040.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:25][CH2:24][CH:21]2[CH2:23][CH2:22]2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: NCC1CC1
Product: CCCN(CC(=O)NCC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and 1-cyclopropylmethane amine: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.00 (bs, 1H), 3.99 (s, 2H), 3.43 (t, J=7.7 Hz, 2H), 3.12 (t, J=6.8 Hz, 2H), 1.70 (m, 2H), 0.99 (t, J=7.5 Hz, 3H), 0.87 (m, 1H), 0.44 (m, 2H), 0.13 (m, 2H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=[S:15].N>ClCCl.CO>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:14]([NH2:16])=[S:15])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(N)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCCCOc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Pentyloxyaniline (370 ml, 2 mmol) in dichloromethane (3 ml) is added to a solution of 1,1′-thiocarbonyldiimidazole (537 mg, 3 mmol) in dichloromethane (5 ml) at room temperature and the mixture is stirred at room temperature for 30 minutes. 2 N Ammonia in methanol (30 ml) is added to the solution, and the solution is stirred for additional 1 hour at room temperature. The solvent is removed, and the product extracted with ethylacetate and H2O. The crude product is recrystallized from dichloromethane and hexane to afford the thiourea as a white solid. 1H NMR (300 Hz, CDCl3) δ 7.92 (s, 1H, NH), 7.15 (d, J=8.4 Hz, 2H, Aryl H), 6.92 (d, J=8.4 Hz, 2H, Aryl H), 6.0 (br s, 2H, NH2), 3.95 (t, J=6.6 Hz, 2H, CH2), 1.79 (m, 2H, CH2), 1.44-1.38 (m, 4H, (CH2)2), 0.94 (t, J=7.2 Hz, 3H, CH3). MS (APCI) m/z 239 [M+H]±.