Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[N:6]=1.[F:11][CH:12]([F:27])[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21](O)=[C:20]([CH3:26])[CH:19]=2)[N:14]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][C:21]2[C:20]([CH3:26])=[CH:19][C:18]([C:15]3[N:14]=[C:13]([CH:12]([F:11])[F:27])[O:17][N:16]=3)=[CH:23][C:22]=2[CH3:24])[S:9][N:8]=1
Reactant: Cc1cc(-c2noc(C(F)F)n2)cc(C)c1O
Reactant: Cc1nsc(CCCO)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nsc(CCCOc2c(C)cc(-c3noc(C(F)F)n3)cc2C)n1
Temperature: 20 °C
Yield: 81 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (242 mg, 1.53 mmol), 4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol described in allowed U.S. patent application Ser. No. 07/869,287, incorporated herein by reference (400 mg, 1.67 mmol) , and DEAD (290 mg, 1.67 mmol) was dissolved in 16 mL of THF. To the above solution was added triphenylphosphine (438 mg, 1.67 mmol) at 0° C. and the mixture was allowed to warm to 20° C. overnight. The solvent was removed in vacuo, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride (7×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (10 cm column, ethyl acetate/hexane, from 1/6 to 1/4) followed by recrystallization from ethyl acetate/hexane to afford 471 mg (81%) of 3-methyl-5-[3-[4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole, as a white crystalline solid, m.p. 62°-64° C. 3-Methyl-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole (I, Thi=3-methyl-1,2,4-thiadiazol-5-yl, Y=1,3-propylene, R1 =R2 =methyl, R3 =5-methyl-1,2,4-oxadiazol-3-yl)
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[F:24][C:25]([F:36])([F:35])[C:26]1[N:30]2[CH2:31][CH2:32][NH:33][CH2:34][C:29]2=[N:28][N:27]=1>>[CH3:23][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([N:33]1[CH2:32][CH2:31][N:30]2[C:26]([C:25]([F:36])([F:24])[F:35])=[N:27][N:28]=[C:29]2[CH2:34]1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Yield: 38.1 %

Procedure:
The title compound was prepared from (3R)-3-[(1,1-dimethylethoxy-carbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.1 mg, 0.15 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (39.2 mg, 0.20 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate) to afford the title compound (29 mg) as a solid. 1H NMR (500 MHz, CDCl3) δ 1.37 (s, 9H), 2.61˜3.00 (m, 4H), 3.92˜4.30 (m, 5H), 4.93 (s, 1H), 4.95˜5.12 (m, 1H), 5.22˜5.35 (br, 1H), 6.83˜6.95 (m, 1H), 7.02˜7.12 (m, 1H). LC/MS (M+1-t-Bu) 452.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:35])=[O:34]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(=O)(=O)c3ccccc3F)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 15 mg (0.11 mmol) 2-fluorobenzenesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.[CH2:31]1[CH:35]2[CH2:36][CH2:37][CH2:38][CH:34]2[CH2:33][NH:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:31]1[CH:35]2[CH2:36][CH2:37][CH2:38][CH:34]2[CH2:33][N:32]1[C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:21]=1)=[O:27]
Reactant: C1CC2CNCC2C1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC5CCCC5C4)ncn3)CC1)C(=O)N2
Temperature: 0 °C

Procedure:
80 mg (0.20 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 40 mg (0.27 mmol) octahydrocyclopenta[c]pyrrole hydrochloride, 0.080 mL (0.57 mmol) TEA and 80 mg (0.25 mmol) TBTU were stirred in 0.9 mL DMF overnight at RT. The reaction mixture was combined with saturated sodium hydrogen carbonate solution and ice water, and the precipitated solid was suction filtered and dried.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[CH:5]=1.[H][H]>[Pd].CO>[NH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([N:2]([CH3:16])[CH3:1])=[O:15])=[CH:5][C:6]=1[CH3:14]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)N(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N(C)C)cc(C)c1N

Procedure:
10% Palladium on carbon (100 mg) is added to a solution of N,N,3,5-tetramethyl-4-nitrobenzamide (1 g) in methanol (10 mL) and the mixture is hydrogenated for 3 hours under 2 bar hydrogen pressure. Then the catalyst is filtered off and washed with methanol. The combined mother liquors are concentrated to give the title compound. Yield: 1 g; LC (method 20): tR=2.75 min; Mass spectrum (ESI+): m/z=193 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH2:23][CH2:22][C:21]=2[CH:25]=1>>[O:24]1[C:20]2[CH:19]=[CH:18][C:17]([C:2]#[C:1][C:3]3[CH:15]=[CH:14][C:6]4[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=4[CH:4]=3)=[CH:25][C:21]=2[CH2:22][CH2:23]1
Reactant: Ic1ccc2c(c1)CCO2
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CC1(C)COc2ccc(C#Cc3ccc4c(c3)CCO4)cc2OC1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 5-iodo-2,3-dihydro-benzofuran. MS (ESI) 320.1 (M•)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH:31]3[CH:29]([CH2:30]3)[CH2:28]2)[CH:24]=[N:25][CH:26]=1)=[O:14])(C)(C)C.ClC(O[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH2:37]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:28][CH:29]3[CH:31]([CH2:30]3)[CH2:32]2)[CH:24]=[N:25][CH:26]=1)=[O:14])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(N2CC3CC3C2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@H]1COc1cncc(N2CC3CC3C2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.7 %

Procedure:
A mixture of CF3COOH, H2O, and CH2Cl2 (10:1:40, 153 mL) was added to a 250 mL round-bottom flask containing 3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-azabicyclo[3.1.0]hexane (6.00 g, 15.8 mmol). The flask was capped with a glass stopper, and the reactants were stirred at room temperature for 14 h. The reaction mixture was concentrated with a rotary evaporator (bath up to 35° C.) and was further dried with an oil pump (35° C.). The residue was dissolved in water (30 mL) and THF (100 mL). The mixture was stirred in an ice bath. Aqueous NaOH solution (5 N, approximately 20 mL) was added dropwise to adjust the pH of the solution to 10 (as monitored by spotting a few μL of the solution on pH paper). Benzyl chloroformate (4.9 mL, 31.6 mmol, 2.0 equiv.) was added dropwise over 30 min. During the addition, the pH of the solution was kept between 9 and 10 by gradually adding 5 N NaOH solution (approximately 20 mL). The pH of the solution was adjusted to 10 at the end of the addition. The ice bath was removed, and the mixture was stirred at room temperature for 18 h. The product was extracted into EtOAc (150+2×100 mL). The combined organic phases were concentrated, and the residue was purified by CC (SiO2, 25×3.8 cm, EtOAc/hexanes 3:1) to give the product as a colorless oil (4.00 g, 67%). 1H NMR (CDCl3, 500 MHz) δ 7.68 (br s, 1H), 7.63 (s, 1H), 7.38-7.26 (m, 5H), 6.40 (br s, 1H), 5.13 (s, 1H, J=12.2 Hz), 5.09 (s, 1H, J=8.8 Hz), 4.65-4.58 (m, 1H), 4.50-4.23 (m, 1H), 4.17-4.10 (m, 1H), 4.06-3.96 (m, 2H), 3.51 (d, 2H, J=8.8 Hz), 3.40 (d, 1H, J=8.3 Hz), 2.47-2.32 (m, 2H), 1.70 (t, 2H, J=3.4 Hz), 0.79 (td, 1H, J=7.6, 4.9 Hz), 0.33 (q, 1H, J=3.8 Hz). MS (EI) m/z 379 (M+, 10%), 288 (1.9%), 177 (4.8%), 176 (9.1%), 175 (11%), 148 (5.0%), 91 (100%). The product of a second run solidified on standing at room temperature; mp 80-81.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CBr
Reactant: Cc1cccc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C)cccc1C
Reaction time: 8 h

Procedure:
65 g of 2,6-dimethylphenol are dissolved in 200 ml of dry DMF and, under N2, 23.2 g of a 55% suspension of sodium hydride in mineral oil are added in portions. Then 50.4 ml of methyl bromoacetate are added dropwise with stirring, and the mixture is left to stand overnight. The precipitated salt is filtered off with suction, and the filtrate is concentrated. The residue is taken up in ethyl acetate, and the solution is extracted with water. The organic phase is dried over magnesium sulfate and concentrated. An oily liquid remains and is used directly in the following reaction.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:27][N:26]=1>>[CH2:33]([O:32][C:30]([C:28]1[S:29][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[N:26][N:27]=1)=[O:31])[CH3:34]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCOC(=O)c1nnc(N)s1
Product: CCOC(=O)c1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)s1
Yield: 43.1 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl (5-amino-1,3,4-thiadiazole-2-carboxylate) (58.9 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (31.9 mg).
Reaction SMILES: Cl.Cl.Cl[CH2:4][C:5]1[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:35])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:4][C:5]4[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CN(C)Cc1nc(CCl)cs1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 15 %

Procedure:
N-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.050 g, 0.220 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.074 g, 0.220 mmol) were suspended in DMF (4 mL) and potassium carbonate (0.152 g, 1.10 mmol) was added. The mixture was stirred at room temperature for 50 h and then at 70° C. for 3.5 h. An additional portion of N-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and the mixture was stirred at 70° C. for a further 25 h. The reaction mixture was concentrated in vacuo. and the residue was partitioned between ethyl acetate and brine. The organic portion was washed with 1 N aqueous sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated in vacuo. to afford a brown solid. Recrystallization from ethyl acetate/diethyl ether afforded the title compound as a pale brown solid (0.016 g, 0.033 mmol, 15% yield). 1H NMR (400 MHz; CDCl3): 2.37 (s, 6H); 3.79 (s, 2H); 4.00 (s, 3H); 5.34 (s, 2H); 7.00 (s, 1H); 7.15 (br s, 1H); 7.34-7.37 (m, 2H); 7.55 (d, 1H); 7.57 (d, 1H); 7.96 (d, 1H); 8.66 (s, 1H); MS (EI) for C22H21Cl2N5O2S: 490 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)=[C:2]=[O:3].OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>CN(C=O)C>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1][C:2](=[O:3])[NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=5)=[O:33])[CH2:28]4)[CH2:25][CH2:26]3)=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)Nc3ccc4c(c3)OCO4)CC2)C1
Reaction time: 8 h

Procedure:
5-Isocyanato-benzo[1,3]dioxole (Aldrich, 50 mg, 0.302 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (150 mg, 0.302 mmol) and TEA (127 μL, 0.906 mmol) in DMF (3 mL) at room temperature. The reaction was stirred overnight and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:43][CH3:44])=[C:10]([CH2:19][NH:20][C:21](=[O:42])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=O)[CH:35]=4)[C:30]([F:33])=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:45][C@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:43][CH3:44])=[C:10]([CH2:19][NH:20][C:21](=[O:42])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:34]4[CH:35]=[CH:36][CH:40]=[C:38]([CH2:37][N:50]5[CH2:49][CH2:48][NH:47][C@@H:46]([CH3:45])[CH2:51]5)[CH:39]=4)[C:30]([F:33])=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]propanediamide (36.0 mg, 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and to the filtrate was added MeOH (2.0 mL) and 1 drop of concentrated HCl. The solution was heated at 60° C. for 12 h. Purification was completed via reverse phase HPLC (acidic conditions) using a Gilson. The product was dissolved in 3 mL MeOH and went through a 0.5 g amine column (washed with 8 mL MeOH) to afford 16.3 mg of the title compound (38.9%). LC-MS m/z 700 (M+H)+, 0.66 min (ret time).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:36])=O>C(Cl)Cl>[Cl:36][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(CO)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(c1ncccc1CNc1nc(Nc2ccc(CCl)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A suspension of 6 (800 mg, 1.66 mmol) in DCM (5 mL) was cooled to 0° C. and treated with a solution of thionyl chloride (0.266 ml, 3.65 mmol) in DCM (2.0 mL). The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for 20 hours. The reaction mixture was then treated with DCM and washed with water (2×). The aqueous layer was collected and washed with DCM. The combined organic layers were then dried over MgSO4, filtered and concentrated to provide 7 as a white solid. Yield: 668 mg, 80%. 1H NMR (500 MHz, d6-DMSO) δ: 6.68 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.64 (m, 2H), 7.42 (m, 3H), 7.14 (d, 2H), 4.82 (d, 2H), 4.66 (s, 2H), 3.17 (s, 3H), 3.15 (s, 3H). FAK IC50: 0.00155 μM (Table 1, Example 348)
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[O:27]1CCCC1>>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][CH2:2][CH2:3][OH:27])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:9][C:8]2=[O:10])[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](CC)c2ccc(Br)cc2)C(=O)O1
Product: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.242 mmol) in tetrahydrofuran (10 mL) was added BH3 THF (3 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. Then the reaction was quenched by water, followed by 3 mol/L NaOH and H2O2 (3 mL). The PH of the mixture was adjusted to <7 with 5% HCl. The organic phase was separated, extracted by EtOAc, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (15 mg, 15%). LC-MS Method 3 tR=1.36, min, m/z=432, 434; 1H NMR (CDCl3): δ=0.99 (t, 3H), 1.29 (m, 1H), 1.63 (m, 1H), 1.98 (m, 4H), 2.20-2.42 (m, 2H), 2.48 (m, 1H), 3.08 (m, 1H), 3.49 (m, 1H), 5.30 (m, 1H), 6.92 (m, 2H), 7.26 (m, 4H), 7.35 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][CH:22]([CH2:24][CH2:25][CH:26](Br)[CH3:27])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:26]([CH3:27])[CH2:25][CH2:24][CH:22]([Br:21])[CH3:23])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)CCC(C)Br
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(Br)CCC(C)Oc1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[Cl:10])[C:5]#[N:6].[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@H:14]1[OH:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:11][C:8]1[C:9]([Cl:10])=[C:2]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@H:14]2[OH:23])[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: COC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: N#Cc1cc(Br)c(Cl)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COC(=O)N1CC[C@@H](Nc2cc(C#N)cc(Br)c2Cl)[C@H](O)C1
Temperature: 105 °C
Yield: 10.2 %

Procedure:
A mixture of 3,5-dibromo-4-chlorobenzonitrile (160 mg, 0.542 mmol), (3R,4R)-methyl 4-amino-3-hydroxypiperidine-1-carboxylate (88 mg, 0.505 mmol), Pd2(dba)3 (69.4 mg, 0.076 mmol), BINAP (47.2 mg, 0.076 mmol), and Cs2CO3 (494 mg, 1.516 mmol) in a dry microwave vial was flushed with nitrogen. Toluene (3.7 mL) was added and the vial was sealed and heated at 105° C. for 4 hours. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine and dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography eluting with hexane containing 20% to 50% EtOAc afforded (3R,4R)-methyl 4-((3-bromo-2-chloro-5-cyanophenyl)amino)-3-hydroxypiperidine-1-carboxylate (20 mg).