Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH3:22])=[O:20])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:24][O:25][CH2:26][CH2:27][OH:28].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>>[F:23][C:14]1[CH:15]=[C:16]([C:19]([NH:21][CH3:22])=[O:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:3]1[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=1[C:5]([NH:24][O:25][CH2:26][CH2:27][OH:28])=[O:7]
Reactant: CNC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: CNC(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 45 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-{2-fluoro-4-[(methylamino)carbonyl]anilino}benzoic acid with 2-(aminooxy)ethanol and DMT-MM by the general procedure of Example 3, Step B, then purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 2-{2-fluoro-4-[(methylamino)carbonyl]anilino}-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a crystalline cream solid (45%); m.p. (acetone) 197-200° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.86 (br s, 1 H), 8.31 (br q, J=4.3 Hz, 1 H), 7.65 (dd, J=12.6, 1.8 Hz, 1 H), 7.55 (dd, J=8.4, 1.8 Hz, 1 H), 7.47-7.41 (m, 1 H), 7.27 (dd, J=16.9, 9.5 Hz, 1 H), 6.84 (ddd, J=8.6, 8.6, 4.8 Hz, 1 H), 4.72 (v br s, 1 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.8 Hz, 2 H), 2.76 (d, J=4.5 Hz, 3 H). Anal. calcd. for C17H16F3N3O4: C, 53.3; H, 4.2; N, 11.0. Await Found.
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C)=O.[NH2:32][CH:33]([C:35]1[N:40]=[N:39][C:38]([NH:41][C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:37][CH:36]=1)[CH3:34].[N+:54]([C:57]1[NH:61][C:60]([C:62](O)=[O:63])=[CH:59][CH:58]=1)([O-:56])=[O:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[N+:54]([C:57]1[NH:61][C:60]([C:62]([NH:32][CH:33]([C:35]2[N:40]=[N:39][C:38]([NH:41][C:42]3[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=3)=[N:37][CH:36]=2)[CH3:34])=[O:63])=[CH:59][CH:58]=1)([O-:56])=[O:55]
Reactant: O=C(O)c1ccc([N+](=O)[O-])[nH]1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc([N+](=O)[O-])[nH]3)nn2)cc(OC)c1OC
Yield: 75.6 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 5-nitro-1H-pyrrole-2-carboxylic acid (132 mg, 0.85 mmol), diisopropylethylamine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave 5-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (218 mg, 75%) as a yellow solid. MS m/z 443 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13](I)=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13]([NH:32][CH2:33][CH2:34][OH:35])=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: NCCO
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(I)s1
Solvent: CC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(NCCO)s1

Procedure:
94 mg (0.159 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(2-iodo-1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were initially charged in 2.5 ml of acetone, 0.479 ml (7.927 mmol) of 2-aminoethanol was added
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([F:14])=[CH:12][C:11]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([F:14])=[CH:12][C:11]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 55.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (118 mg, 0.190 mmol) prepared in Example 107f, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (50 mg, 56%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH3:36])=[O:5])[CH3:2].C1(C)C=CC=CC=1.[C:44](Cl)([Cl:46])=[O:45]>>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:44]([Cl:46])=[O:45])[CH2:8][C@@H:7]1[CH3:36])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)Cl)C[C@@H]1C
Yield: 76 %

Procedure:
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (prepared in a manner analogous to the procedures described for Examples 3A-3E) (146 mg, 0.28 mmol) was dissolved in 2 mL of a 1.93M phosgene solution in toluene (3.9 mmol). After heating at reflux for 1.5 h, the sample was concentrated in vacuo to afford the title product (125 mg, 76%). 1H NMR (CDCl3) δ 1.2-1.6 (m, 7H), 2.2-2.4 (m, 1H), 4.2-4.6 (m, 4H), 5.2-5.6 (m, 2H), 7.1 (s, 1H), 7.5-7.9 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(CCC(N)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To 10 ml of the solution of 0.35 g of methyl 4-[3-amino-3-(3-pyridyl)propyl]benzoate in dichloromethane were added 0.22 ml of triethylamine and 0.33 g of p-chlorobenzene sulfonylchloride, and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water, which was then extracted with dichloromethane, washed in saturated aqueous sodium chloride, and dried over magnesium sulfate. The residue was subjected to chromatography on a silica gel column, to obtain 0.34 g of methyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]benzoate. The spectrometric data supports the structure of [36] as follows.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24]N5CCCCC5)[C:18](=[O:31])[CH:17]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.FC(F)(F)C(O)=[O:39]>O>[O:31]=[C:18]1[CH:17]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][N:9]=[C:10]3[CH:15]=2)[CH:21]=[CH:20][N:19]1[CH2:22][CH2:23][CH:24]=[O:39]
Reactant: O=c1cc(-c2ccn3c(-c4ccccc4)cnc3c2)ccn1CCCN1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=CCCn1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1=O

Procedure:
To a solution of 4-(3-phenylimidazo[1,2-a]pyridin-7-yl)-1-(3-piperidin-1-ylpropyl)pyridin-2(1H)-one (0.210 g, 0.503 mmol) in 5.0 mL of a 2:1 solution of chloroform: (50% trifluoracetic acid:water) at 0° C. After 1 hour solvent was removed under reduced pressure to give 3-[2-oxo-4-(3-phenylimidazo[1,2-a]pyridin-7-yl)pyridin-1(2H)-yl]propanal. 1H NMR (CDCl3) δ 8.94 (s, 1H), 8.90 (d, 1H, J=6.84 Hz), 8.05 (s, 1H), 7.73–7.64 (m, 6H), 7.60 (m, 4H), 4.90 (t, 2H, J=5.13 Hz), 2.60 (m, 2H). LCMS m/z (M+1) Calc: 344.1, found 344.0
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Br:18])[CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: Nc1cccc(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 3-bromoaniline (0.806 g, 4.69 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(3-bromo-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.65 g, 100%).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Na].[CH2:27]([OH:29])[CH3:28]>>[CH2:14]([C:3]1[C:4](=[O:13])[C:5]2[C:10]([C:11](=[O:12])[C:2]=1[O:29][CH2:27][CH3:28])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: CCO
Agent: [Na]
Product: CCCCCCCCCCCCC1=C(OCC)C(=O)c2ccccc2C1=O

Procedure:
Eight parts of 3-chloro-2-n-dodecyl-1,4-naphthoquinone were added in one portion to a solution of 0.54 parts of sodium metal dissolved in 100 parts of ethyl alcohol at ambient temperature. The resulting dark suspension was heated at reflux for two hours. Excess ethyl alcohol was removed in vacuo and the dark residue was recrystallized from 2-propanol to yield 7.6 parts of 2-n-dodecyl-3-ethoxy-1,4-naphthoquinone, m.p. 36°-38° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10](O)=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][OH:11])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1CCO
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of 2-(4,5-difluoro-2-methoxyphenyl)acetic acid (1 g, 4.95 mmol) in THF (20 mL) at 0° C. was added 1M LAH (9.89 mL, 9.89 mmol) in THF and the resulting mixture was heated at 60° C. for 3 h. Mixture was then cooled and quenched with dropwise addition of water (0.5 mL), 1N NaOH (0.5 mL), and then 1 mL H2O. After stirring for 15 min. the mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was dried under high vacuum to afford 2-(4,5-difluoro-2-methoxyphenyl)ethanol (800 mg, 4.25 mmol, 86% yield) as a clear viscous oil. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.02 (t, J=9.8 Hz, 1H), 6.71 (dd, J=12.1, 6.7 Hz, 1H), 3.87-3.82 (m, 2H), 3.81 (s, 3H), 2.85 (t, J=6.5 Hz, 2H), 1.56 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[H-].[Na+].[CH3:23]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-cyclopentyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 124 mg, 3.1 mmol) at 0° C., followed by the dropwise addition of methyl iodide (0.193 mL, 3.1 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and used for next step reaction. [M+H] calc'd for C14H18ClFN4O, 313. found 313.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7]C(=O)OC(C)(C)C)(=[O:4])=[O:3].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CCN
Reaction time: 1.5 h

Procedure:
In a dried reaction flask, tert-butyl 2-(methylsulfonyl)ethylcarbamate (0.906 g, 4.06 mmol) was dissolved in dichloromethane (60 mL). Trifluoroacetic acid (27.8 mL) was added dropwise at −10° C. The mixture was stirred for 1.5 hr, and was concentrated at reduced pressure to produce a crude brown oil (1.258 g).
Reaction SMILES: C([N:8]1[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2([CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:13]1[C:10]2([CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:15][NH:8][CH2:9]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)CC12CCC2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CNCC12CCC2

Procedure:
A stirred solution of (+/−)-tert-butyl (6-benzyl-6-azaspiro[3.4]octan-8-yl)carbamate (Intermediate 13, 0.523 g, 1.653 mmol) in ethanol (31.2 mL) with Pd/C (10% b/w) (0.418 g, 3.14 mmol) was hydrogenated for 3 hrs 15 min @ 45 psi. +/−MS after 2 hrs 20 min indicated that the reaction was essentially complete (m/e 227.3, M+H for desired product), 171.1 (M+H-isobutylene); no starting material was detected. The catalyst was removed by filtration through a pad of Celite followed by filtration through VWR 0.45 micron Nylon filter disc. The filtrate was concentrated under vacuum, co-evaporated with CH2Cl2, to yield 0.365 g of the title compound as a viscous yellow oil which became a pale yellow solid on standing under vacuum (0.354 g). +/−MS: m/e 227.3 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.59 (br. s., 1H), 3.94 (br. s., 1H), 3.23 (dd, J=11.4, 6.2 Hz, 1H), 3.02 (d, J=11.0 Hz, 1H), 2.86 (d, J=11.0 Hz, 1H), 2.68 (dd, J=11.4, 3.7 Hz, 1H), 2.16-2.06 (m, 1H), 2.02-1.80 (m, 5H), 1.77 (d, J=2.9 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2cc(C(=O)N3CCCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with pyrrolidine (9 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane and allowed to react overnight. The reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 26 mg of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)c(F)c1
Yield: 98 %

Procedure:
A mixture of 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionic acid (3.45 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionate (3.56 g, yield 98%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.60–2.71 (2H, m), 2.92–3.03 (2H, m), 3.69 (3H, s), 7.22–7.65 (3H, m), 8.23 (1H, s).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C=O.[CH:14](O)=O.Cl>>[CH3:14][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CCOC(=O)C1CCN(C)CC1
Temperature: 25 °C

Procedure:
To ethyl isonipecotate (10 g, 64 mmol) was slowly added a 37% aqueous solution of formaldehyde (10 mL, 128 mmol) followed by formic acid (10 mL, 233 mmol) and the mixture was heated to reflux for about 3 days. The mixture was allowed to cool to room temperature, the pH was adjusted to 2 by addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The pH of the aqueous layer was then adjusted to 11 by addition of 2N aqueous sodium hydroxide, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts of the second extraction were dried (MgSO4), filtered, and concentrated under vacuum to provide the desired product. 1H NMR (500 MHz, CDCl3-d): δ 1.25 (t, J=6 Hz, 3H), 1.40 (m, 1H), 1.59 (m, 1H), 1.62 (m, 1H), 1.95 (m, 2H), 2.06 (m, 1H), 2.26 (s, 3H), 2.71 (m, 1H), 2.94 (m, 1H), 4.13 (dd, J=6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1>>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:9](=[O:18])[CH:10]=[CH:11]2
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: Cc1ccc2[nH]c(=O)ccc2c1

Procedure:
The title compound is prepared from p-toluidine and cinnamoyl chloride according to the procedure described in Synthesis 1975, 739. The crude product obtained is triturated in Et2O/hexanes and filtered to give the title compound as a beige solid which is used in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]C(O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.C([N:31](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(#N)C.O>[NH2:31][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:7][C:2]([CH3:1])([CH3:28])[NH:3][C:4]([CH3:26])([CH3:27])[CH2:5]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCN)cc3)n2)CC(C)(C)N1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propionic acid (100 mg, 0.26 mmol) (Step A of Example 185), triethylamine (37 μl, 0.26 mmol) and diphenylphosphoryl azide (57 μl, 0.26 mmol) in 3 ml acetonitrile was heated for 18 hours at 70° C. Then, 1.2 ml 0.4N-HCl was added and the mixture was stirred for 1 hour at ambient temperature. The solution was diluted with water, extracted with ether and the aqueous phase was made basic with 2N-NaOH. Extraction with EtOAc and purification with preparative HPLC gave the title compound. Yield: 24 mg (26%).
Reaction SMILES: COCCOC.[F:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[C:19]=1[F:26]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:19]1[C:20]([NH2:25])=[N:21][C:22]([CH3:24])=[N:23][C:18]=1[C:13]1[C:8]([F:7])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1nc(N)c(F)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: Cc1nc(N)c(F)c(-c2cccnc2F)n1
Temperature: 100 °C
Yield: 59.7 %

Procedure:
DME (6.00 mL, 57722 μmol) and water (0.6 mL, 3152 μmol) were added to a mixture of 2-fluoropyridin-3-ylboronic acid (666 mg, 4728 μmol), 6-chloro-5-fluoro-2-methylpyrimidin-4-amine (0.5093 g, 3152 μmol), and Pd(Ph3P)4 (364 mg, 315 μmol) under nitrogen. The mixture was sealed and heated at 100° C. for 60 min under microwave irradiation. After cooling, the mixture was diluted with water and the precipitate was collected, washed with DCM, and 5-fluoro-6-(2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (418 mg, 60%) was isolated as an off-white powder. LCMS (API-ES) m/z 223 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.39 (d, J=4.02 Hz, 1H) 8.18 (t, J=8.03 Hz, 1H) 7.53 (t, J=5.27 Hz, 1H) 7.38 (br. s., 2H) 2.37 (s, 3H).