Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a mixture of 0.10 g (0.00022 mole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100), 0.16 mL (0.00090 mole) of ethyldiisopropyl amine and 0.028 g (0.00025 mole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.11 g (0.00025 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-90:10) gave 0.057 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (I-101).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCO1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCO2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[5,6-difluoro-1-(tetrahydro-pyran-2-ylmethyl)-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown powder (32%). MS (Turbo Spray): m/z=512.4 (M+H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(N)CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cc(-c2c(-c3ccco3)nn3c(NC4CCCC4)cccc23)ccn1
Agent: NC1CCCC1
Product: c1coc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)c2)c1
Yield: 584.7 %

Procedure:
N-Cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine (0.05 g, 0.02 mmol) was dissolved in cyclopentylamine (1 mL and heated) in a 135° C. oil bath for 4 days. The amine was removed in vacuo. The product was purified by silica gel chromatography (7:1 hexane:ethyl acetate) to give 25 mg (42%) of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine. 1H NMR (CDCl3) δ 8.1 (d, 1H), 7.51 (s, 1H), 7.17 (t, 1H), 6.94 (d, 1H), 6.69 (m, 2H), 6.5 (s, 1H), 6.45 (m, 1H), 6.00 (d, 1H). 5.95 (d, 1H), 4.6 (br d, 1H), 4.0 (m, 1H), 3.92 (m, 1H), 2.19–2.09 (m, 2H), 2.03–1.95 (m, 2H), 1.88–1.43 (m, 8H), 1.32–1.22 (m, 2H);MS m/z 428 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)c(F)c1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)c(F)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chloro-3-fluorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 206.8-207.4° C. 1H NMR (acetone-d6/300 MHz) 7.92 (s, 1H), 7.74 (s, 1H), 7.59 (m, 1H), 7.16 (m, 1H), 6.99 (m, 1H), 6.83 (s, 1H), 5.86 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, 3F, J=6.5 Hz), −113.8 (m, 1F). Anal. Calc'd for C17H8Cl2F4O4: C, 48.25; H, 1.91; Cl, 16.76. Found: C, 48.20; H, 1.97; Cl, 16.92.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]=[C:19]2[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][C:23]=3[NH:22][C:21](=[O:29])[N:20]2[CH:30]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[CH2:27][CH2:28][C:23]2[NH:22][C:21](=[O:29])[N:20]3[CH:30]=[C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[N:18]=[C:19]3[C:24]=2[CH2:25]1
Reactant: Fc1ccccc1CBr
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CN(Cc1ccccc1F)CC2
Reaction time: 0.75 h

Procedure:
2-Fluorobenzyl bromide (54 uL, 0.45 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (128 mg, 0.45 mmol) and triethylamine (76 uL, 0.54 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 45 minutes, and then concentrated. Aqueous sodium bicarbonate was added, the aqueous layer extracted twice with 10% methanol/ethyl acetate, and the combined organic layers dried over magnesium sulfate, filtered, concentrated, and triturated with methanol/ether to give 9-(2-Fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 13) as an off-white solid, m.p. 270°-273° C. Treatment with ethanolic HCl affords the corresponding HCl salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([F:10])=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([NH:20][CH2:21][CH:22]=[CH2:23])[CH:18]=[CH2:19]>C(#N)C.C(OCC)(=O)C.O>[CH2:17]([N:20]([CH2:21][CH:22]=[CH2:23])[CH2:2][C:3]([C:5]1[S:6][C:7]([F:10])=[CH:8][CH:9]=1)=[O:4])[CH:18]=[CH2:19]
Reactant: C=CCNCC=C
Reactant: O=C(CBr)c1ccc(F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C=CCN(CC=C)CC(=O)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a stirred solution of 2-bromo-1-(5-fluorothiophen-2-yl)ethanone (13.28 g, 59.53 mmol) in acetonitrile (298 mL) at 0° C. under nitrogen is added potassium carbonate (10.70 g, 77.39 mmol) and diallylamine (9.54 mL, 77.39 mmol). The mixture is allowed to slowly warm to room temperature with stiffing over 16 hours then diluted with ethyl acetate (500 mL) and water (200 mL). The phases are separated and the aqueous phase extracted twice with ethyl acetate (100 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with hexanes/ethyl acetate (9:1) to give the title compound (12.45 g, 87%) as a yellow oil. ES/MS (m/e): 240 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([C:30](=[N:32]O)[NH2:31])[CH:29]=1.CCN(C(C)C)C(C)C>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([C:30]2[N:31]=[C:11]([C:10]3[CH:14]=[CH:15][C:16]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[C:8]([CH3:7])[CH:9]=3)[O:13][N:32]=2)[CH:29]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCC1
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3)c(C)c2)n1

Procedure:
Oxalyl chloride (139 μL; 1.64 mmol; 3 eq.), Intermediate 33 (120 mg; 0.55 mmol; 1 eq.), Intermediate 23 (101 mg; 0.55 mmol, 1 eq.) and DIEA (283 μL; 1.64 mmol; 3 eq.) were reacted according to general procedure 2. Purification by preparative HPLC (increasing amount of 0.1% TFA in CH3CN, in 0.1% TFA in water) afforded the title compound as a white solid.
Reaction SMILES: 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+].[CH3:53][O:54][C:55](=[O:85])[CH:56]([C:61]1[CH:62]=[C:63]([C:75]2[CH:80]=[CH:79][C:78]([C:81]([F:84])([F:83])[F:82])=[CH:77][CH:76]=2)[CH:64]=[C:65](OS(C(F)(F)F)(=O)=O)[CH:66]=1)[CH2:57][CH:58]([CH3:60])[CH3:59].[NH:86]1[C:94]2[C:89](=[CH:90][CH:91]=[CH:92][CH:93]=2)[CH2:88][CH2:87]1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:53][O:54][C:55](=[O:85])[CH:56]([C:61]1[CH:62]=[C:63]([C:75]2[CH:76]=[CH:77][C:78]([C:81]([F:83])([F:84])[F:82])=[CH:79][CH:80]=2)[CH:64]=[C:65]([N:86]2[C:94]3[C:89](=[CH:90][CH:91]=[CH:92][CH:93]=3)[CH2:88][CH2:87]2)[CH:66]=1)[CH2:57][CH:58]([CH3:59])[CH3:60]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCc3ccccc32)c1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A solution of Pd(OAc)2 (6 mg, 0.025 mmol) and rac-BINAP (23 mg, 0.037 mmol) in THF (2.5 mL) was stirred under nitrogen for 10 min. Cs2CO3 (95 mg, 0.29 mmol), 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (100 mg, 0.21 mmol) and indoline (0.028 mL, 0.25 mmol) were added and the reaction mixture was stirred under nitrogen at 65° C. for 48 h. The solution was then partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried (MgSO4) and concentrated to yield an oil. The residue was purified by flash chromatography (0 to 10% EtOAc in petroleum ether) to give the title compound. The resulting oil was used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.II>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]2[S:17][S:17][CH:16]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:18])[N:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Agent: II
Solvent: CCO
Product: O=C1C2=C(CCCC2)C(SSC2C3=C(CCCC3)C(=O)N2c2ccc(Cl)cc2F)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
In 20 ml of ethanol was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one and 1.4 g of iodine was added to the solution, followed by stirring at room temperature for 5 hours. Upon cooling, there resulted crystals, which were recovered by filtration, washed with ethanol and dried, thereby producing 1.7 g (yield of 57%) of the subject compound. Recrystallization from acetone yielded white crystals, m.p. 146°-147° C.
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]2[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])C=CC=CC=1>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])[C:14](=[O:23])[C@H:13]1[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:1]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ozone was passed through a -78° C. CH2Cl2 (650 mL) solution of compound 4a (55 g, 84 mmol) until a blue color was maintained. Excess ozone was purged with N2Dimethyl sulfide (60 mL) was added. The solution was allowed to warm to room temperature and to stand for 48 h. The solution was concentrated to afford the title compound which was not further purified but used directly in step B.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[C:12]([O:16][C:17](=[O:23])[NH:18][CH2:19][CH:20](O)[CH3:21])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[F:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:6]=1)[O:11][CH:20]([CH3:21])[CH2:19][NH:18][C:17](=[O:23])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-5-fluorophenol (3.0 g) and tert-butyl-N-(2-hydroxypropyl)carbamate were dissolved in THF (20 ml) and triphenylphosphine (7.5 g) and di-tert-butyl-azodicarboxylate were added. The exothermic reaction was cooled in an ice bath. Then the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel/dichloromethane: petroleum ether 1:2). The fractions were combined and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1M NaOH. The organic layer was separated, dried, filtered and concentrated in vacuo.
Reaction SMILES: C([N:8]([C@H](C1C=CC=CC=1)C)[C@@H:9]([C:13]1[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH2:10][CH2:11][OH:12])C1C=CC=CC=1.CC(O)=O.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]([C:13]1[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH2:10][CH2:11][OH:12]
Reactant: Cc1ccc([C@@H](CCO)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc([C@H](N)CCO)cn1
Reaction time: 1 h

Procedure:
To a solution of (R)-3-(benzyl((S)-1-phenylethyl)amino)-3-(6-methylpyridin-3-yl)propan-1-ol (2.1 g, 5.83 mmol) in HPLC MeOH (40 mL), were added AcOH (0.34 mL, 5.8 mmol), Pd(OH)2 (0.42 g) and HCOONH4 (1.8 g, 29.16 mmol) and was heated to reflux. After 1 h, the reaction mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (neutral Al2O3, aq. NH3/MeOH/CH2Cl2, 1:20:80) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:16].C[Mg+].[Br-].[Li]C(C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=1)[CH:29]=[O:30]>C1COCC1.CO>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]([OH:30])[C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=2[F:16])[CH:31]=[CH:32][N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c(F)c1
Reactant: O=Cc1ccnc(Cl)c1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(O)c2ccnc(Cl)c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a solution of tert-butyl 4-bromo-3-fluorophenylcarbamate (2.60 g, 9.0 mmol) in anhydrous THF (30 mL) at −78° C. was added MeMgBr (3.0 M in Et2O, 3.1 mL, 9.3 mmol) via syringe. The solution was stirred for 10 min at that temperature, and then warmed to 0° C. for 0.5 h. After the solution was cooled back to −78° C., a solution of t-BuLi (1.7 M in hexane, 10.6 mL, 18.1 mmol) was added over 4 min. The resulting solution was allowed to stir for 5 min before a solution of 2-chloroisonicotinaldehyde (1.41 g, 10 mmol) (for preparation, see Frey, L. F. et al. Tetrahedron Lett. 2001, 42, 6815) in anhydrous THF (25 mL) was added in 3 min. The reaction mixture was stirred at −78° C. for 20 min and 2.0 mL of MeOH was added. The solution was then concentrated under reduced pressure and the residue was dissolved in 200 mL of EtOAc. It was subsequently washed with H2O (2×50 mL), brine (2×50 mL) and dried over MgSO4. After filtration and concentration, the residue was purified by flash chromatography on SiO2 eluting with 0%-50% EtOAc in hexane to give tert-butyl 4-((2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate (1.30 g, 41% yield). MS(ESI+): m/z 353.28/355.24 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1)=[O:2].P([O-])(O)(O)=[O:33].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(OCC)(=O)C.O1CCCC1.O.C(O)(C)(C)C>[C:28]([O:27][C:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:4]3[C:3]([C:1]([OH:33])=[O:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:22][CH:21]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C=O)c2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C(=O)O)c2)cc1
Temperature: 0 °C
Yield: 71.9 %

Procedure:
To a mixture of tert-butyl 3-[4-(2′-formylbiphenyl-3-ylmethoxy)phenyl]propanoate (1.5 g, 3.60 mmol), sodium dihydrogenphosphate (0.43 g, 3.60 mmol), 2-methyl-2-butene (1.72 mL, 16.2 mmol), tert-butanol (7 mL), water (15 mL) and tetrahydrofuran (15 mL) was added sodium chlorite (1.22 g, 10.8 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was diluted with ethyl acetate, washed with water, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) to give the title compound (1.12 g, 72%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:14]C(=O)C)([CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18]>>[ClH:18].[ClH:18].[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:13])([NH2:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Agent: Cl
Product: CC1(N)CCN(Cc2ccccc2)C1

Procedure:
A mixture of N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (4.01 g, 17.2 mmol) and conc HCl (50 mL) was heated at reflux for 2 d. The mixture was evaporated under reduced pressure to leave 1-benzyl-3-methylpyrrolidin-3-amine dihydrochloride salt as a brown tar.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH:29]3[CH2:31][CH2:30]3)=[CH:19][N:18]=2)=[O:16])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([CH2:4][C:5]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])[C:20]([CH:29]3[CH2:31][CH2:30]3)=[CH:19][N:18]=2)=[O:16])([CH3:13])[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.5 %

Procedure:
To a solution of tert-butyl 3-cyclopropyl-2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-methyl-propanoate (example 186c, 103 mg, 233 μmol) in dichloromethane (0.5 ml) was added TFA (159 mg, 108 μl, 1.4 mmol). The reaction mixture was stirred at room temperature for 14 hours. Volatiles were removed in vacuo and the residue was dissolved in a mixture of dichlormethane and toluene followed by evaporation to dryness. The procedure was repeated twice until a precipitate formed. The precipitate was dried under high vacuum to yield the title compound (95 mg) as a crude solid which was used without any purification. MS (ESI, m/z): 387.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccc(F)c(Cl)c1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-chloro-4-fluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)=[C:11]([CH3:41])[CH:10]=1)([CH3:7])[CH3:6])#[N:4].Cl>O1CCCC1>[C:3]([C:5]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)=[C:11]([CH3:41])[CH:10]=1)([CH3:7])[CH3:6])#[N:4]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC(C)(C)C#N)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OC(C)(C)C#N)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 M aqueous LiOH solution (500 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(4-(2-cyanopropan-2-yloxy)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (130 mg) in tetrahydrofuran (2 mL). The mixture is stirred at room temperature for 48 hours. 1 N Hydrochloric acid (500 μL) is added and the residue is purified by HPLC on reversed phase. The product thus obtained is chromatographed on silica gel (petrole ether/ethyl acetate 80:20→20:80) to give the title compound. Yield: 23 mg; LC (method 12): tR=0.67 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:28])[NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21]3)[CH2:10][C@@H:9]1[OH:29])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([NH:15][C:14]([C@@H:11]3[CH2:12][CH2:13][C@@H:8]([NH2:7])[C@@H:9]([OH:29])[CH2:10]3)=[O:28])[CH:17]=[CH:18][CH:19]=2)[N:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)Nc2cccc3ccc(C#N)nc23)C[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2cccc(NC(=O)[C@@H]3CC[C@@H](N)[C@@H](O)C3)c2n1
Yield: 67.1 %

Procedure:
A solution of carbamate (i) (2.4 g, 6 mmol) in dichloromethane (50 mL) was treated with trifluoroacetic acid (10 mL). After 18 hours the mixture was evaporated and partitioned between saturated aqueous sodium bicarbonate solution and 20% methanol/dichloromethane. The aqueous phase was twice more extracted and the combined extracts dried and evaporated giving a solid. This was triturated with ether/ethyl acetate (1/1) and filtered, washing with ether, to afford a light brown solid (1.25 g, 61%).