Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)[CH:35]=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:34]([CH3:35])[CH3:33])=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)O)CC3)cc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) Dimethylamine hydrochloride (0.0373 g, 0.000457 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 331, analyzed by rHPLC. MS: (ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 6.34 (s, 1H), 6.01-5.79 (m, 1H), 4.50 (d, J=10.0 Hz, 4H), 3.53 (s, 4H), 3.18 (s, 2H), 3.03 (s, 3H), 2.82 (s, 3H), 1.47 (d, J=6.5 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[C:13]([F:30])=[C:14]([C:26]([Cl:29])=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1)=[O:16])[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].CC[N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:12]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:14]([C:15]([C:17]2[CH:22]=[N:21][C:20]([C:23](=[O:24])[NH2:35])=[CH:19][CH:18]=2)=[O:16])[C:13]=1[F:30])[CH2:10][CH3:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(C(=O)O)nc2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(C(N)=O)nc2)c1F

Procedure:
To a solution of 5-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid (Example 19)) in dichloromethane (8 ml) was added ammonium chloride (0.057 g, 0.65 mmol), DIPEA (0.137 mL, 0.78 mmol) and then HATU (0.06 g, 0.156 mmol) and the reaction stirred for 1 h. Further HATU totalling (0.12 g, 0.312 mmol) added. The reaction performed on a further (57 mg), both reactions combined and diluted with dichloromethane washed with water. The organic extract was dried (Na2SO4), filtered and concentrated. Purified by Prep HPLC to give {(R)-1-[3-(6-Carbamoyl-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (0.042 g) MS: [M+H] 436 {(R)-1-[3-(6-Carbamoyl-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (0.042 g, 0.137 mmol) treated with saturated HCl/EtOAc stirred at ambient for 1 hour, precipitate filtered and washed with ether to give 5-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid amide (0.025 g).
Reaction SMILES: [ClH:1].[CH:2]1([C@H:8]2[N:13]3[CH:14]=[C:15]([C:20]([N:22]4[CH2:27][C@H:26]([CH3:28])[NH:25][C@H:24]([CH3:29])[CH2:23]4)=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[ClH:1].[CH:2]1([C@H:8]2[N:13]3[CH:14]=[C:15]([C:20]([N:22]4[CH2:23][C@H:24]([CH3:29])[N:25]([CH3:32])[C@H:26]([CH3:28])[CH2:27]4)=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[C@@H]1CN(C(=O)c2cn3c4c(cccc24)OC[C@H]3C2CCCCC2)C[C@H](C)N1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(C(=O)c2cn3c4c(cccc24)OC[C@H]3C2CCCCC2)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-dimethylpiperazin-1-yl-carbonyl]pyrrolo[1,2,3-de]-1,4-benzoxazine hydrochloride salt (100 mg, 0.26 mmol) in ethanol (10 ml) was added formaldehyde (37% in water; 1 ml, 12.5 mmol) and sodium triacetoxyborohydride (200 mg, 0.93 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was purified by flash chromatography eluting with 1-10% (v/v) methanol in dichloro-methane to afford the title compound as the free base. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether; 2 ml) to the free base in dichloromethane (1 ml). The precipitate was filtered and dried to afford the title compound (1:1 hydrochloride salt). EsIMS: m/z=396.1 [M+H]+, 268; [α]D22−19.6° (c=2.1 mg/ml in methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[C:14]#[N:15]
Reactant: CN(C)CCCl
Reactant: N#CCc1coc(-c2ccc(F)cc2)n1
Agent: Cl
Product: CN(C)CCC(C#N)c1coc(-c2ccc(F)cc2)n1
Yield: 48 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile and 2-chloro-N,N-dimethylethanamine hydrochloride as described in example 16 step 1b (400 mg, yield 48%). 1H NMR (400 MHz, MeOD) δ 8.10-8.07 (m, 2H), 7.99 (m, 1H), 7.29-7.25 (t, J=8.9 Hz, 2H), 4.24-4.20 (t, J=7.3 Hz, 1H), 2.59-2.46 (m, 2H), 2.29 (s, 6H), 2.23-2.17 (m, 2H). MS (ESI) m/z: Calculated for C15H16FN3O: 273.13. found: 274.2 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C@H:4]([O:12][CH3:13])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][O:12][C@@H:4]1[CH2:3][C@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:7][CH2:6][C@@H:5]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@@H](O)C[C@H]1OC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A solution of methyl (1S,2R,4R)-4-hydroxy-2-methoxycyclohexanecarboxylate (racemic) (1.14 g, 6.06 mmol) in dichloromethane (30 mL) was treated with methanesulfonyl chloride (0.938 mL, 12.1 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h and partitioned between ethyl acetate and water. The organic phase was concentrated and purified on silica gel (eluting with 50% ethyl acetate in hexanes) to give the desired product (1.48 g, 93%). 1H NMR (400 MHz, CDCl3) δ 4.89 (1H, m), 3.70 (3H, s), 3.62 (1H, m), 3.36 (3H, s), 3.02 (3H, s), 2.78 (1H, m), 2.42 (1H, m), 2.01 (2H, m), 1.98 (1H, m), 1.80 (1H, m), 1.62 (1H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38](O)(=[O:47])[CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].CCCCCC>C(O)C>[C:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])(=[O:47])[C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CCCCCC
Solvent: CCO
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)[C@@H](O)c2ccccc2)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (0.50 g) in ethanol (2 mL) was added a mixture of (+)-mandelic acid (148 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added hexane/IPE at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.55 g).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)#[N:29]>C1(C)C=CC=CC=1.ClCCl>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:35])=[CH:32][CH:31]=1)#[N:29]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)NC2=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S2)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 4-cyanobenzoyl chloride (1.2 g) dissolved in a mixed solution of toluene (10 ml) and dichloromethane (2 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:16][CH2:17][C:18]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.1 g of 3-phenylindoline in 60 ml of acetone was cooled to 0° C., 5.1 ml of chloroacetylchloride was added and the mixture poured into an ice cold solution of 10 g of sodium acetate in 50 ml of water. The mixture was then stirred for one hour at room temperature and the residual solid removed by filtration. Recrystallization from ethanol gave a yield of 13.0 g of the desired N-chloroacetyl-3-phenylindoline having a melting point of 76°-78° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[NH2:25])=[CH:20][CH:19]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:27]1([CH2:33][NH:34][C:14]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:26])[NH2:25])=[CH:22][CH:23]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(N)=O)cc2)(C(=O)O)CC1
Reactant: NCC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of solution of 4-(4-carbamoylbenzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.38 mmol; 0.5 g) in DMF (5 mL) was added cyclohexylmethylamine (1.18 mmol; 0.154 mL), N,N-diisopropyl-N-ethylamine (2.81 mmol; 0.50 mL) and HBTU (1.38 mmol; 0.51 g), and the resulting mixture was stirred at room temperature overnight. The mixture was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The residue was dissolved in tetrahydrofuran (2 mL) and a 4N HCl in 1,4-dioxane solution (3 mL), and the resulting mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethyl amide as a hydrochloride salt. MS (ESI) m/z 358.40 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31](O)=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:34])[NH:12][CH:11]3[C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:56][S:57]([NH2:60])(=[O:59])=[O:58].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([NH:60][S:57]([CH3:56])(=[O:59])=[O:58])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:34])[NH:12][CH:11]3[C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (140 mg, 0.22 mmol) and CDI (70 mg, 0.44 mmol) in DMF (2 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (207 mg, 2.2 mmol) and NaH (78 mg, 60%, 2 mmol) in DMF (2 mL), which had been stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the mixture was acidified to “pH” 1-2 by addition of concentrated HCl solution. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (100 mg).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:23]1([CH2:29][C:30](N)=[NH:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N>C(O)C.CCOCC>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[O:1]([CH:8]([CH3:11])[CH2:9][NH:10][C:30](=[NH:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)Oc1ccccc1
Reactant: N=C(N)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCO
Solvent: CCOCC
Product: CC(CNC(=N)Cc1ccccc1)Oc1ccccc1

Procedure:
2-Phenoxypropylamine (6.0 g.) was added to a suspension of phenylacetamidine p-toluenesulphonate (12.4 g.) in absolute ethanol (20 ml.). The mixture was heated to reflux for 4 hours by which time the initially vigorous evolution of ammonia had practically ceased. The resulting solution was cooled somewhat and diluted with ether to give an oil which rapidly crystallised on scratching. The solid was filtered and recrystallised from a mixture of ethanol and water to give N-(2-phenoxypropyl)phenylacetamidine p-toluenesulphonate, m.p. 127°-129°.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>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.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH2:19])[CH3:22]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ncccc1C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 2-chloronicotinate (23 g), tributyl(1-ethoxyvinyl)tin (64 mL) and toluene (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (7.3 g), and the mixture was stirred overnight at 80° C. under an argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (27 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([NH:21]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(O)C.[ClH:33]>C(O)C>[ClH:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Yield: 94 %

Procedure:
To a solution of 1,1-dimethylethyl (1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate (2.58 g, 6.24 mmol) in ethanol (35 ml) was. added 20% hydrogen chloride ethanol solution (35 ml) and the mixture was heated under reflux for 30 min. The reaction solution was evaporated under reduced pressure and the residue was washed with diethyl ether. to give (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (2.05 g, 94%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:18])=[CH:9][CH:8]=1.[F:19][C:20]([F:30])([F:29])[C:21]([NH:23][C@@H:24]([C:26](O)=[O:27])[CH3:25])=[O:22]>ClCCl>[CH3:18][O:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:6][CH3:5])=[CH:8][C:9]=1[C:26](=[O:27])[C@H:24]([NH:23][C:21](=[O:22])[C:20]([F:19])([F:29])[F:30])[CH3:25]
Reactant: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: COc1ccc(OC)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)[C@@H](C)NC(=O)C(F)(F)F)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a suspension of AlCl3 (3.8 g, 28.6 mmol) in dichloromethane (100 mL) was added a solution of 1,4-dimethoxynaphthalene (4.88 g, 25.9 mmol) in dichloromethane (50 mL). To this mixture was added a solution of (R)-N-trifluoroacetylalanine (16 g, 86.5 mmol) in CH2Cl2 (50 mL); this mixture was stirred at room temperature for 3 h. The reaction mixture was poured slowly into ice (200 g) to quench the reaction and the organic layer was separated and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane: 1/9) to give a yellow oil (3 g): 1H NMR (DMSO-d6) δ 1.24 (d, 3H, CH3), 3.93 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 5.51 (m, 1H), 6.99 (s, 1H, Ar—H), 7.96 (m, 2H, Ar—H), 8.17 (m, 2H, Ar—H), 9.83 (d, NH); MS 356 (M+1).
Reaction SMILES: [N:1]1([CH:6]2[CH:10]([OH:11])[CH2:9][NH:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:8]2[CH2:9][C@@H:10]([OH:11])[C@H:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:7]2)=[N:17][CH:18]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OC1CNCC1N1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CN(c2ccc(Br)cn2)C[C@H]1N1CCCC1
Yield: 67.6 %

Procedure:
Dissolve [1,3′]bipyrrolidinyl-4′-ol (452 mg, 2.89 mmol) in acetonitrile (10 mL) and add 5-bromo-2-fluoro-pyridine (764 mg, 4.34 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol). Reflux the mixture for 3 days. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Combine the organic fractions, dry over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-7.5% methanol (2N NH3)/CH2Cl2 to give 610 mg (67%) of the title compound as a yellow foam. MS/ES m/z (79Br) 312.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([NH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][O:24][CH2:25][CH3:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.NCCC(OCC)=O.[CH3:46][NH:47][CH2:48][CH2:49][C:50]([O:52]CC)=[O:51].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([N:47]([CH3:46])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][O:24][CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
A solution of 4-[(cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]benzoic acid (100 mg), ethyl β-alaninate hydrochloride (37 mg), ethyl 3-(methylamino)propanoate (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg), hydroxybenzotriazole monohydrate (37 mg) and triethylamine (33 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (81 mg, 69%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([F:12])[F:11].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[F:11][C:10]([F:12])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)(COCCCCCCBr)c1ccccc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCOCC(F)(F)c1ccccc1
Temperature: 70 °C
Yield: 48.7 %

Procedure:
To a solution of Intermediate 7 (10.9 g, 34 mmol) in dimethylformamide (23 mL) was added potassium phthalimide (7.56 g, 40.8 mmol) and a catalytic amount of (n-hexadecyl)tri-n-butylphosphonium bromide. The mixture was heated at 70° C. for 3 hours. The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with methylene chloride yielded the title compound (6.41 g, 49%) as oil.