Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)s1
Agent: NCCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(Br)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.100 g, 0.378 mmol) and 5-(4-bromophenyl)thiophene-2-carbaldehyde (0.101 g, 0.378 mmol) in acetic acid 5 mL is added β-alanine (3.37 mg, 0.038 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.120 g, 0.234 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.84 (m, 1H), 7.63 (m, 1H), 7.50 (m, 3H), 7.15 (m, 6H), 6.69 (s, 1H), 5.66 (dd, J=11.4, 5.1 Hz, 1H), 3.69 (dd, J=14.4, 12.0 Hz, 1H), 3.51 (dd, J=10.5, 5.1 Hz, 1H). MS (ES+, m/z): 511.3 (M−−1, 100.0).
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:7])C=CN=C1.[CH3:13][O:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C(O)=O>ClCCl>[N:8]1([C:6](=[O:7])[CH:15]([O:14][CH3:13])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COC(C(=O)O)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(C(=O)n1ccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Di-(1H-imidazol-1-yl)methanone (1.073 g, 6.62 mmol) was added in small portions to a stirred solution of 2-methoxy-2-phenylacetic acid (1.047 g, 6.30 mmol) in dichloromethane (3 mL) at room temperature under argon. The reaction mixture was stirred at room temperature overnight. The mixture was washed twice with water, dried over MgSO4 and concentrated yielding 1-(1H-imidazol-1-yl)-2-methoxy-2-phenylethanone (1.118 g, 82%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=O)[C:14]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.CN(C)C1C=CC(C)=CC=1.P(Br)(Br)(Br)=O.[NH2:41][NH2:42]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16]=[C:15]([NH:41][NH2:42])[C:14]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc2c(c1)C(=O)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(NN)=NCc1c(-c3nc(C4CC4)no3)ncn1-2
Yield: 38 %

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methoxy-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (1 g, 3 mmol) and N,N-dimethyl-p-toluidine (0.856 mL, 5.9 mmol) were mixed in toluene (25 mL), treated with phosphoryl bromide (0.935 g, 3.3 mmol), and refluxed for 15 h. Toluene was evaporated and the residue extracted with CH2Cl2 (50 mL) and water (50 mL). The organic layer was dried, evaporated, redissolved in THF (50 mL), and treated with a 1 M solution of anhydrous hydrazine in TBF (10 mL, 10 mmol) at reflux overnight. The mixture was evaporated and directly chromatographed on silica gel in CH2Cl2/MeOH 10:1. One obtained a light brow solid (0.4 g, 38%). m/z 352 (MH+).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCOC(=O)CCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1
Yield: 78 %

Procedure:
Sodium metal (3.6 g, 0.16 m) was dissolved in ethanol (250 ml) and 4-nitrothiophenol (25 g, 0.13 m) was added to it. To the above mixture was added ethyl chloroacetate (16.0 g). After refluxing for 1 hr, the suspension was filtered. The filtrate was concentrated (50 ml) and allowed to cool, precipitation occurred. The product was collected and dried under vacuum to afford yellow crystals 78% yield, mp. 43°-45° C. It was characterised by spectroscopic analysis.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][C:24]([S:30][CH3:31])=[N:25][CH:26]=2)[N:21]1[CH3:32].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][C:24]([S:30]([CH3:31])=[O:9])=[N:25][CH:26]=2)[N:21]1[CH3:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1-n1c(=O)c2cnc(SC)nc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1-n1c(=O)c2cnc(S(C)=O)nc2n1C
Reaction time: 1 h

Procedure:
At 0° C., 68 mg of m-chloroperbenzoic acid was added to a chloroform solution of 91 mg of 2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 1 hour. Aqueous saturated sodium hydrogencarbonate solution was added thereto, and extracted with chloroform to obtain crude 2-(2-methoxyphenyl)-1-methyl-6-(methyl sulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[NH2:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1.C(N(CC)CC)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:69][C:51]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:37]1[CH2:38][CH2:39][N:40]=[C:36]1[NH:35][C:51]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:18]=2)[CH:3]=1)=[O:69]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: Nc1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(=O)NC3=NCCS3)c2s1
Temperature: 90 °C

Procedure:
Ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (200 mg, 0.37 mmol) and 2-aminothiazole (111 mg, 1.11 mmol) were stirred in DMF (3 ml) and triethylamine (3 ml) was added. Carbon monoxide was bubbled through the mixture for 10 min. Xantphos (86.3 mg, 0.15 mmol) and palladium (II) acetate (18 mg, 0.08 mmol) were added and the reaction was purged with carbon monoxide, sealed then heated to 90° C. for 18 h. The reaction was allowed to cool and the solvents removed under reduced pressure. The resulting residue was triturated with water causing a solid to precipitate which was isolated by filtration to afford the target material (185 mg, 80% pure by LC-MS) (86%) after drying in a vacuum oven. This material was used directly in the next step with no further purification.
Reaction SMILES: [C:1]([N:5]([C@@H:9]1[CH2:14][C:13]2[C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:17]=[C:18]([F:19])[C:12]=2[O:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([CH:38]=[O:39])C.[CH3:40][OH:41]>>[C:1]([N:5]([C@@H:9]1[CH2:14][C:13]2=[C:15]([C:40]([O:39][CH3:38])=[O:41])[CH:16]=[CH:17][C:18]([F:19])=[C:12]2[O:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCCN([C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1)C(C)(C)C
Reactant: CO
Solvent: CCN(CC)CC
Product: CCCN([C@H]1COc2c(F)ccc(C(=O)OC)c2C1)C(C)(C)C
Temperature: 70 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
(R)-3-(N-tert-Butyl-N-n-propylamino)-8fluoro-5-trifluoromethylsulfonyloxy-3,4-dihydro-2H-1-benzopyran (1.4 g, 3.3 mmol) and triethylamine (1.0 mL, 7.4 mmol) were dissolved in a solution of DMF/MeOH (6:2; 30 mL) and then degassed followed by the inlet of carbon monoxide (4×). With a slight positive pressure of carbon monoxide, palladium(II)-acetate (0.030 g) and 1,3-bis(diphenylphosphino)propane (0.060 g) were added and the reaction mixture was degassed and subjected to carbon monoxide once again. The reaction was heated to 70° C. (oil-bath temperature) under carbon monoxide atmosphere with vigorous stirring for 12 h. GC indicating an incomplete reaction (68% product vs. 21% starting material), the solution was cooled and then filtered through Celite. More palladium(II)-acetate (0.030 g) and 1,3-bis(diphenylphosphino)propane (0.060 g) were added and the reaction was resumed as described above. After another 3 h GC indicated a slight improvement of the ratio (77% vs. 12%) and the reaction was allowed to cool. The following day the solvent was removed in vacuo. The remaining red-brown oil was taken into saturated aqueous NaHCO3 and then extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the crude ester. Flash chromatography on silica [eluent: EtOAc (15 and 30%) in hexane] gave 0.178 g of starting material and 0.842 g (89% yield based on recovered starting material) of the title compound as a clear oil. [α]21D =-121.1° (C=0.9; CHCl3). GC-MS (70 eV) M=323 (14%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:23]C(OCC2C=CC=CC=2)=O)[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][C:10]=1[C:34]([CH3:37])([CH3:36])[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[NH2:23][CH:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:11]=1)[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(C)(C)c1cc(CC(CNS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(CC(N)CNS(C)(=O)=O)ccc1OCc1ccccc1
Yield: 76 %

Procedure:
N-[3-(4-benzyloxy-3-tert-butylphenyl)-2-benzyloxycarbonylaminopropyl]methanesulfonamide (1.2 g, 2.29 mmol) was dissolved in a mixture of methanol (23 ml) and methylene chloride (5 ml), mixed with palladium hydroxide/carbon (0.60 g) and stirred for 12 hours in a hydrogen atmosphere. After filtering off insoluble material using Celite, the filtrate was concentrated to give crude N-[2-amino-3-(4-benzyloxy-3-tert-butylphenyl)propyl]methanesulfonamide (0.68 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:17]2=[CH:18][CH:19]=[N:20][CH:21]=[C:16]2[C:5]2[C:6]([OH:15])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3]1.[ClH:23].[N:24]1([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:23].[CH3:22][C:2]1([CH3:1])[C:17]2=[CH:18][CH:19]=[N:20][CH:21]=[C:16]2[C:5]2[C:6]([O:15][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(1-pentyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(1-pentyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N—((R)-2,3-dihydroxypropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=498.2 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]2[C:30]3([CH2:40][O:41][C:24]=2[CH:23]=1)[C:38]1[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32][C:31]3=[O:39].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]2[C:30]3([CH2:40][O:41][C:24]=2[CH:23]=1)[C:38]1[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[N:32]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:31]3=[O:39]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (55%): mp 108-109° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.66 (m, 1H), 7.29-7.20 (m, 3H), 7.15-7.03 (m, 3H), 6.93-6.90 (m, 1H), 6.79-6.76 (m, 1H), 5.26-4.85 (m, 4H); MS (ES+) m/z 371.9 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:9][C:4]1[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)O)C2)n1
Temperature: 140 °C

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1.397 g, 8.52 mmol), (3S)-3-piperidinecarboxylic acid (1 g, 7.74 mmol) and Hunig's base (2.70 ml, 15.49 mmol) in NMP (10 mL) was heated in the microwave at 140° C. for 90 minutes. LCMS showed mainly desired product. The reaction was cooled down to room temperature, and poured onto water (160 mL). The formed solid was filtered, and the filtered solid was identified as the SM 4,6-dichloro-2-pyrimidinamine. The product stayed in the aqueous solution. 1N HCl was added to adjust the pH=7. Then the aqueous solution was extracted 3× with a mixture of CHCl3 and isopropanol (200:10 mL). The organic layers were combined and evaporated to afford the title compound (1.99 g) as a yellow solid. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:48]=[C:49]([CH3:51])[CH3:50]>C(#N)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1)[CH2:48][C:49]2([CH3:51])[CH3:50])=[O:12]
Reactant: O=Cc1cccc(Br)c1
Reactant: C=C(C)C
Reactant: COC(=O)c1cc(F)ccc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 57.1 %

Procedure:
A mixture of 2-amino-5-fluoro-benzoic acid methyl ester (12.1 g, 71.4 mmol), 3-bromo-benzaldehyde (13.2 g, 71.4 mmol) and ytterbium(III) triflate hydrate (4.4 g, 71.4 mmol) in acetonitrile (200 mL) was cooled to 0° C. in a sealed reaction bottle. Then a cooled solution of isobutene (28 g, 500 mmol) was added into. The reaction mixture was heated to 90° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (16 g, 57%) as a white solid: MS (ESI) M+1=392.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]=[N:9][OH:10].ClN1C(=O)CCC1=O.[CH:20]1([C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.O1CCCC1.O>[CH:20]1([C:24]2[O:10][N:9]=[C:8]([C:7]3[C:6]([Cl:11])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)CC(=O)C1CCC1
Reactant: ON=Cc1c(Cl)cncc1Cl
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (3.15 g, 16.5 mmol) in N,N-dimethylformamide (13 mL) was added N-chlorosuccinimide (2.20 g, 16.5 mmol). The mixture was heated to 65° C. and all solids dissolved. The solution was stirred at 65° C. for approximately 1.5 hours, poured into water and extracted with ether. The ether layer containing the crude imidoyl chloride was washed with brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (3.37 g, 19.8 mmol) in tetrahydrofuran (4 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 6.21 mL, 19.8 mmol) and the mixture was stirred for approximately 7 minutes. Then the above imidoyl chloride was added in tetrahydrofuran (13 mL) at a slow rate. A solid precipitated and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was concentrated and taken up with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and purified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (2.98 g, 53%). 1H-NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 4.35-4.20 (m, 1H), 4.05 (q, J=7 Hz, 2H), 2.45-2.30 (m, 4H), 2.14-2.04 (m, 1H), 2.00-1.89 (m, 1H), 0.96 (t, J=7 Hz, 3H). LRMS (APCI) m/z 341 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:38]([C:36]2[N:37]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[S:34][CH:35]=2)=[O:39])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1csc(-c2ccccc2F)n1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-fluorophenyl)thiazole-4-carboxylic acid (see Bioorg. Med. Chem. Lett. 2010, 20, 1758) gave 322. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.53 (s, 1H), 8.52-8.44 (m, 1H), 7.89 (s, 1H), 7.63-7.56 (m, 1H), 7.51-7.37 (m, 2H), 4.88 (dd, J=10.6, 3.6 Hz, 1H), 4.57-4.39 (m, 1H), 4.38-4.25 (m, 1H), 4.20-3.99 (m, 1H), 3.79 (s, 3H), 2.13-2.05 (m, 1H), 1.90-1.78 (m, 1H), 1.75 (d, J=9.6 Hz, 3H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][CH:15]2[CH2:18][F:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[C:24]([O:23][C:21]([NH:20][C@@:13]12[CH2:14][CH:15]([CH2:18][F:19])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC(CF)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]12CNC[C@H]1C(CF)C2
Yield: 99.5 %

Procedure:
(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derived from isomer B) (305 mg, 806 μmol) was dissolved in tetrahydrofuran (6 mL). 20% palladium hydroxide-carbon (50% wet) (100 mg) was added, and the mixture was stirred in a hydrogen atmosphere for one hour. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1 M sodium hydroxide solution was added to the residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 196 mg of the title compound as a colorless syrup.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[C:7]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27](CC3C=CC([O:44][CH3:45])=CC=3)CC3C=CC(OC)=CC=3)[N:21]=2)[C:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].OS([C:50]([F:53])([F:52])[F:51])(=O)=O.[OH-:54].[Na+]>C(O)(C(F)(F)F)=O>[F:51][C:50]([F:53])([F:52])[C:45]([OH:44])=[O:54].[NH2:1][C:2]([C:5]1[CH:6]=[C:7]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=2)[C:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)(C)N)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
A solution of 4-(5-(2-aminopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.025 g, 0.041 mmol) in TFA (1 mL) was treated with triflic acid (0.029 mL, 0.330 mmol), sealed, and heated at 80° C. for 2 h. The reaction was cooled and treated with ice and 10 N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (5-50% MeCN/H2O with 0.1% TFA). Product-containing fractions were concentrated in vacuo to give 4-(5-(2-aminopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine 2,2,2-trifluoroacetate (9 mg, 0.019 mmol, 45.5% yield) as an orange solid. m/z (ESI, +ve ion) 367 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.76 (s, 1H); 8.93 (d, J=2.7 Hz, 1H); 8.54 (d, J=2.5 Hz, 1H); 8.50 (d, J=2.7 Hz, 1H); 8.37 (br. s., 3H); 8.13 (dd, J=8.8, 2.7 Hz, 1H); 7.90 (br. s., 1H); 7.80 (br. s., 1H); 6.84 (d, J=9.0 Hz, 1H); 3.85 (s, 3H); 2.45 (s, 3H); 1.68 (s, 6H).