Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:39][CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: BrCCCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(CCCc2ccccc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-butanamide (Example 51, Step A) and 3-phenylpropyl bromide by the procedure described in Example 3, Step A. 1H NMR (200 MHz, CDCl3): 1.38 (s,6H), 1.82 (m,4H), 2.4-2.9 (m,7H), 3.45 (m,1H), 4.36 (m,1H), 5.02 (s,2H), 5.64 (s,1H), 6.69 (d,8 Hz,1H), 6.9-7.4 (m,14H). FAB-MS: calculated for C32H37N3O4 527; found 528 (M+H,100%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(OCC)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])=[O:12]
Reactant: CC(=O)c1ccccc1Cl
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (5.18 g, 32.3 mmol) was slowly added dropwise to a solution of 1-[2-chlorophenyl]ethanone (5.00 g, 32.3 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 2-bromo-1-(2-chlorophenyl)ethanone as an oil quantitatively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17]([N:20]([CH3:22])[CH3:21])OC.CN(C=O)C>O>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=[CH:17][N:20]([CH3:22])[CH3:21])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), dimethoxymethyl-dimethylamine (11.9 g, 100 mmol) and DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The red precipitate was collected via filtration, washed with water adequately and dried to give [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, 63%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:21])=[CH:16][CH:15]=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:21])=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc3c(c2)OCO3)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from 3,4-Methylenedioxybenzene boronic acid and (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 379.4
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=4)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:25][C:22]1[S:21][C:20]([C:15]2[CH:14]=[CH:13][C:12]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=4)[C:10]4[C:18]([C:17]=3[CH:16]=2)=[CH:19][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=4)=[CH:24][CH:23]=1
Reactant: COc1ccc(-n2c3ccc(-c4ccc(C)s4)cc3c3cc(-c4ccc(C)s4)ccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)c2cc(-c4ccc(C)s4)ccc2n3-c2ccc(O)cc2)s1
Temperature: 25 °C
Yield: 96 %

Procedure:
The obtained 3,6-bis(5-methylthiophen-2-yl)-9-(4-methoxyphenyl)carbazole (3.73 g, 8.0 mmol) was dissolved in methylene chloride (30 mL). 1M Methylene chloride solution of boron tribromide (8 mL) was added dropwise to the resultant solution at −10° C., followed by stirring at room temperature. Next, the resultant mixture was washed with water and dried and the solvent was evaporated, to thereby obtain a gray solid. The obtained solid was purified through silica gel column chromatography using as an eluent a solvent mixture of methylene chloride/hexane (4/1 by volume), to thereby obtain 3.47 g of 3,6-bis(5-methylthiophen-2-yl)-9-(4-hydroxyphenyl)carbazole.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][C:37]([CH3:39])=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: CC(C)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@@H]1F
Product: CC(C)N1C[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4S)-4-fluoro-1-(1-methylethyl)pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 322) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C1C=NC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:49][C:50]1[CH:59]=[C:58]2[C:53]([CH2:54][CH2:55][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]2)=[CH:52][CH:51]=1>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:49][C:50]3[CH:59]=[C:58]4[C:53]([CH2:54][CH2:55][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]4)=[CH:52][CH:51]=3)=[O:20])=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (86 mg, 0.24 mmol) in N,N-dimethylformamide (0.5 mL) at ambient temperature was added a 0.6M solution of 7-aza-1-hydroxybenzotriazole in N,N-dimethylformamide (0.5 mL, 0.30 mmol), followed by solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.27 mmol). The resulting solution was stirred at ambient temperature for 1 hour. A solution of tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (66 mg, 0.27 mmol) in N,N-dimethylformamide (0.5 mL) was added. The resulting solution was stirred in an oil bath set to 50° C. for 21 hours. The solution was cooled to ambient temperature and diluted with water (15 mL). After stirring for a few minutes, the resulting precipitate was collected by filtration, washed with water, and dried under vacuum. This crude solid was purified by chromatography on silica gel, eluting with 50/50 hexanes/ethyl acetate, to afford tert-butyl 7-(4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate as an orange oil (84 mg, 59% yield).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a stirred solution of 66.4 g (0.4 mole) ethyl 4-hydroxybenzoate in 100 ml acetone, under a nitrogen atmosphere was added 55.3 g (0.40 mole) finely powdered potassium carbonate and 53.2 g (0.44 mole) allyl bromide and the resulting mixture was heated at reflux overnight. After cooling to room temperature the mixture was filtered, washing with ethyl ether. The filtrate and washings were washed with water, brine and dried (MgSO4). Evaporation of solvent in vacuo gave 82.3 g of product as a clear oil. 1H-NMR(CDCl3)ppm(delta): 5.0-5.5 (m), 5.8 (m), 6.8 (m), 8.0 (m).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:26])[C:6]=2[N:7]=1.[NH:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:40]=2)[CH:35]=[CH:34]1>>[OH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:9]3[S:10][C:5]4[C:4]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:3][C:2]([C:38]5[CH:37]=[C:36]6[CH:35]=[CH:34][NH:33][C:41]6=[N:40][CH:39]=5)=[N:7][C:6]=4[C:8]=3[CH3:26])[CH:12]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 4-hydroxypiperidine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone (72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 29.5 mg of 425. MS (Q1) 555.2 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[CH:19]=[C:20]([CH:31]=[C:32]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)[CH:33]=2)[O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:49](Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([O:27][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([O:21][C:20]2[CH:31]=[C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=3)[CH:33]=[C:18]([C:16](=[O:17])[NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][CH2:11]3)[CH:19]=2)=[CH:23][CH:24]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)OCc4ccccc4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.2 %

Procedure:
0.6 g (1.05 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-phenoxy]-benzoic acid was dissolved in 5 ml of DMF. At 0° C. 50 mg (0.35 mmol) of potassium carbonate followed by 45 mg (0.26 mmol) benzylbromide were added and the reaction mixture was stirred for 4 h at RT. Reaction progress was monitored by TLC. Upon completion of the reaction the contents were diluted with 50 ml of ice-water and extracted with 3×50 ml of ethyl acetate, dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude residue was purified by column chromatography using 60-120 mesh silica-gel and eluted with ethylacetate:hexane (1:9) to give 0.38 mg of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 5.36 (2H, s), 6.76 (1H, d), 7.22 (5H, m), 7.46 (7H, m), 7.88 (2H, d), 8.05 (2H, d), 8.36 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH3:10])[CH:7]=1
Reactant: Cc1cc(Br)cnc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Br)cn(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 5-bromo-2-hydroxy-3-methyl pyridine A1 (1.000 g; 5.053 mmol) and potassium carbonate (1.397 g; 10.105 mmol) in DMF (5.000 ml) is carefully added iodomethane (0.346 ml; 5.558 mmol). The reaction mixture is stirred overnight (16 h) at room temperature. The reaction mixture is then quenched with 10% ammonia solution (10 ml) and 30 ml water is added. It is extracted with 3×50 ml EtOAc. The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 150 °C
Yield: 16.1 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (120 mg, 0.346 mmol) from Step 4 of Example 70, (1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol), and DIEA (89 mg, 0.692 mmol) in anhydrous DMA (2.5 mL) was heated in a Biotage microwave synthesizer at 150° C. for 30 min. LCMS analysis indicated that the reaction was incomplete. Additional (1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol) and DIEA (89 mg, 0.692 mmol) were added and the mixture was further heated in a Biotage microwave synthesizer at 150° C. for 2 h. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (24 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.40-8.50 (m, 2H), 8.09 (dd, J=2.6, 9.4 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H), 7.32-7.39 (m, 1H), 7.10-7.31 (m, 5H), 5.47-6.00 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.30 (d, J=3.6 Hz, 1H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 432 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][CH3:15])[CH2:9][C@H:10]([OH:13])[CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][CH3:15])[CH2:9][C@H:10]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](O)C[C@@H](CC)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C[C@H](C[C@@H](CC)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 86.1 %

Procedure:
To a solution of ((1R,3S)-1-ethyl-3-hydroxy-pent-4-enyl)-carbamic acid tert-butyl ester (0.541 mmol; 124 mg) and imidazole (2.164 mmol; 147 mg) in DMF (1.8 mL) is added tert-butyldimethylsilyl chloride (1.623 mmol; 245 mg) at room temperature under N2. After 12 hours, the reaction mixture is quenched with water, extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give [(1R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-1-ethyl-pent-4-enyl]-carbamic acid tert-butyl ester (160 mg, 86%); ESI-MS m/z: 288 [M+−tBu+2], Retention time 5.77 min (condition B).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C@H:21]([CH2:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C@H:21]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36]2)[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3.20 g (6.3 mmol) of 2-(R)-(3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl) propionic acid, benzyl ester (from Step A) in 40 mL of THF at 0° C. was treated with 10 mL of 1.0 M tetrabutylammonium fluoride solution in THF. The resulting mixture was warmed to rt and stirred for 2.5 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of 50% sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on 100 g of silica gel using 2:1 v/v hexanes/ether as the eluant afforded 2.34 g (94%) of the title compound: 1H NMR (500 MHz) δ 1.56-2.07 (8H), 2.15 (br s, 1H), 2.27-2.37 (2H), 2.64 (t, J=11.0, 1H), 2.80 (dd, J=6.5, 11.0), 3.04-3.11 (2H), 3.23-3.30 (2H), 3.56 (dd, J=7.5, 13.0, 1H), 3.68 (dd, J=5.5, 13.0, 1H), 5.15 (ABq, J=20.0, 2H), 7.17-7.40 (1OH).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:14]=[C:15]([S:19]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.40 g, 83%). 1H-NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 6.56 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.35 (s, 1H), 2.22 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[Cl:11])[NH:4][CH:3]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[Cl:11])[N:4]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:3]=1
Reactant: Clc1c(-c2ccccc2)cnc2[nH]cc(Br)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)c(-c3ccccc3)cnc21
Reaction time: 0.33 h
Yield: 95 %

Procedure:
3-Bromo-4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.30 g, 4.23 mmol) was placed in DMF (10 mL) at 0° C. NaH (0.203 g, 5.07 mmol) was then added, and the reaction was stirred for 20 minutes. Benzenesulfonyl chloride (0.595 mL, 4.65 mmol) was then added, and the reaction was stirred for 30 minutes at 0° C. The reaction was then poured into water and extracted with EtOAc. The combined organic fractions were dried, filtered, concentrated and purified (2:1 D CM: hexanes) to give 3-bromo-4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (1.80 g, 95.1% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[N:25]([CH3:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[N:22]=1.C(NC(C)C)(C)C>CS(C)=O>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[N:25]([CH3:26])[C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Product: Cn1c(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)nc2ccccc21
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1138 g, 0.404 mmol), 2-chloro-1-methyl-1H-benzo[d]imidazole (0.081 g, 0.485 mmol), and diisopropylamine (0.211 ml, 1.212 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.577 ml) and heated to 120° C. to stir for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNiH2O, gradient 10% to 100% over min. Fractions containing product were collected and concentrated. Residue taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge to remove any salts to give the title compound (103 mg, 0.027 mmol, 6.79 yield). LCMS showed product peak at 1.57 min (m+1=376.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.03 (m, 2 H) 1.04-1.11 (m, 2 H) 2.47 (d, J=3.33 Hz, 1 H) 2.98 (tt, f=7.04, 3.72 Hz, 1 H) 3.27 (dt, J=13.30, 8.12 Hz, 2 H) 3.56 (s, 3 H) 4.53-4.66 (m, 1 H) 5.24 (quin, J=8.31 Hz, 1 H) 6.89-6.99 (m, 2 H) 7.02 (d, J=6.46 Hz, 1 H) 7.13-7.19 (m, 1 H) 7.19-7.25 (m, 1 H) 7.96-8.00 (m, 1 H) 8.00-8.04 (m, 1 H)