Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[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:33][CH2:34][CH3:35])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[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:33][CH2:34][CH3:35])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[S:47])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Temperature: 60 °C
Yield: 64.5 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.15 mmol) and P2S5 (70 mg, 0.31 mmol) was heated at 60° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM for 2 times. The DCM solution was combined and concentrated. The residue was purified by flash column to give the title compound as white solid (65 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH:24]2[CH2:25][CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Sodium triacetoxyborohydride (0.71 g) was added to a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (0.50 g), N-benzylethanolamine (0.40 g) and acetic acid (0.38 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→60% ethyl acetate/hexane) to give the title compound (0.74 g, 92%) as a pale-yellow oil.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8].[NH3:19]>C(O)C>[NH2:19][CH2:2][C@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(C)(OCC)P(=O)(C[C@@H](O)CCl)OCC
Reactant: N
Solvent: CCO
Product: CCOC(C)(OCC)P(=O)(C[C@@H](O)CN)OCC
Yield: 26 %

Procedure:
A solution of ethyl (2R)-(3-chloro-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 4 days and at 60° C. for one further day. The solution was evaporated and the residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (5-8% MeOH) containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. The aqueous layer was pH adjusted by the addition of a few mL of 10% aqueous Na2CO3 and repeatedly extracted with methylene chloride. The combined organic layers were dried over Na2SO4 and evaporated to give 1.2 g (26%) of ethyl (2S)-(3-amino-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ 4.40-4.55 (b, 1H), 4.10-4.30 (m, 2H), 3.55-3.80 (m, 4H), 3.20-3.30 (m, 1H), 3.00-3.10 (m, 1H), 2.00-2.40 (m, 2H), 1.45-1.53 (dd, J=3.4, 11.7 Hz, 3H), 1.30-1.40 (m, 3H), 1.15-1.25 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[P:10]1(=[O:18])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:16][C:13]1([CH3:17])[CH2:14][O:15][P:10](=[O:18])([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)[O:11][CH2:12]1
Reactant: OCC1CC=CCC1
Reactant: CC1(C)COP(=O)(Cl)OC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)COP(=O)(OCC2C=CCCC2)OC1

Procedure:
A 100 mL round bottom flask equipped with a stirrer bar was charged with 15.04 g (0.134 mol) 3-cyclohexene-1-methanol, 22.52 g (0.122 mol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one, and 10.6 g (0.134 mol) of pyridine. After the above mixture was reacted at 80° C. for 3 hrs. The reaction mixture was added to chloroform (100 mL), and then washed with chloroform (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[C:17](Cl)(Cl)=[O:18]>>[N:1]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1)=[C:17]=[O:18]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)ccc1C(=O)OC(C)(C)C
Product: COc1cc(N=C=O)ccc1C(=O)OC(C)(C)C

Procedure:
tert-Butyl 4-isocyanato-2-methoxy-benzoate was prepared from tert-butyl 4-amino-2-methoxy-benzoate and phosgene using the procedure of step 2 of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:30][C:31]([C:34]1[N:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1)([F:33])[CH3:32]>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:40]([C:37]3[CH:36]=[N:35][C:34]([C:31]([F:33])([F:30])[CH3:32])=[CH:39][N:38]=3)=[O:41])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: CC(F)(F)c1cnc(C(=O)O)cn1
Product: CC(F)(F)c1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-(1,1-difluoroethyl)pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (600 MHz, CDCl3) δ ppm 2.03 (t, J=18.8 Hz, 3H), 2.82 (d, J=12.0 Hz, 1H), 3.14 (d, J=12.4 Hz, 1H), 3.35-3.46 (m, 1H), 3.77-4.07 (m, 1H), 4.20-4.93 (m, 4H), 7.08 (dd, J=11.7, 9.0 Hz, 1H), 7.56 (d, J=4.5 Hz, 1H), 7.80-7.93 (m, 1H), 8.87 (s, 1 H), 9.43 (s, 1H), 9.59 (br. s., 1H)
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:1][C@@H:2]1[C@@H:7]([CH2:8][NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:3]1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNCc2ccccc2)[C@@H](O)C1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A mixture of 1,1-dimethylethyl(3R-trans)-3-hydroxy-4-[[(4-methylphenyl)-sulfonyl]oxymethyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c-I)] (0.03 mol) and benzylamine (0.1 mol) in THF (250 ml) was stirred for 16 hours at 125° C. (autoclave). The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and an aqueous K2CO3 solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE, yielding 5.3 g of 1,1-dimethyl-ethyl (3R-trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate (intermediate 60) ([α]20,D=−68.65° (c=23.16 mg/S ml in CH3OH); mp. 91° C.).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(C(F)(F)F)cc5)cccn4n3)cc2)CC1

Procedure:
[4-(4-Methyl-piperazin-1-yl)-phenyl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.270 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.033 g, 27%). MP=214-216° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44 (d, J=6.5 Hz, 1H), 8.12 (dm J=8.7 Hz, 2H), 7.77 (d, J=7.4 Hz, 2H), 7.59 (d, J=7.4 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.00-6.93 (m, 3H), 6.66 (s, 1H), 3.20-3.15 (m, 4H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=453 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([O:41]C)=[O:40])[CH:36]=[C:35]([O:43][CH3:44])[C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.C(O)C.[OH-].[K+]>O1CCCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:18])([F:19])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([OH:41])=[O:40])[CH:36]=[C:35]([O:43][CH3:44])[C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(OC)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2sc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)nc12
Temperature: 60 °C

Procedure:
The ester, methyl 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylate (161 mg, 0.26 mmol) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL) and subjected to an aqueous solution of potassium hydroxide (100 mg, 2.5 mmol in 2 mL water). The mixture was heated to 60° C. for 2 hr and then the solvent was removed in vacuo. The mixture was diluted with 5% aqueous citric acid and extracted with ethyl acetate (2×100 mL). The organics were dried (MgSO4) then evaporated in vacuo. The product was purified by flash silica chromatography with a gradient of 0-100% ethyl acetate/hexanes to give 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12](O)([C:14](F)(F)F)=O.N1C=CC=CC=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH2:12][CH3:14]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCNc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 87.7 %

Procedure:
5-chloro-2-nitroaniline (17.2 g; 0.1 mole), acetalaldehyde diethyl acetal (Acetal) (21.1 ml; 0.15 mole) and TFA (7.7 ml; 0.1 moles) were dissolved in toluene (500 ml) and stirred for 1 hr. BH3 * pyridine (10.0 ml; 0.1 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40%EtOAc/Hexane. Additional TFA, BH3 * pyridine and acetal were added until the tlc indicated that the 5-chloro-2-nitroaniline was consumed. The reaction mixture was washed 2X with water and placed on a bed of silica and eluted with toluene. The product was the first major component to elute. The product was crystallized from MeOH which produced 17.6 g (88%) of a yellow crystalline solid.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]1[CH:15]=[C:16]([OH:22])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([S:33]([CH3:36])(=[NH:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24]>>[OH:22][C:16]1[CH:15]=[C:14]([NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:35]=[S:33]([C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:32]=[CH:31][CH:30]=4)([CH3:36])=[O:34])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=1
Reactant: COc1cc(O)cc(Nc2ccnc3ccc(Br)cc23)c1
Reactant: CC(=O)Nc1cccc(S(C)(=N)=O)c1
Agent: Cl
Product: COc1cc(O)cc(Nc2ccnc3ccc(N=S(C)(=O)c4cccc(NC(C)=O)c4)cc23)c1

Procedure:
The title compound is prepared starting from 3-(6-bromoquinolin-4-ylamino)-5-methoxyphenol (intermediate 5) and S-(3-acetylaminophenyl)-S-methyl-sulphoximine in analogy to the synthesis of the compound of Example 17 (method D).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[CH2:15][O:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:12])=[CH:5]2.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[CH2:15][O:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:22][CH2:23]1)=[O:12])=[CH:5]2
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1cc2cc(Cl)ccc2[nH]1
Product: CC(C)N1CCC(COCC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 5-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-2-carboxamide (320 mg, 0.72 mmol) and acetone (2.0 mL, 27 mmol) afforded, after purification (SiO2: 0 to 2.5% isopropylamine in 1:1 hexane:EtOAc) and recrystallization (acetonitrile), 185 mg (53%) of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:31]#[C:30][CH2:29][OH:32]
Reactant: Cc1cccc(I)c1C
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C#CCO)c1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1-iodo-2,3-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 19 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-70:30) to give the object product (1.91 g) as a brown oil.
Reaction SMILES: [Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[CH:22][CH:23]=2)=O)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].O.[NH2:32][NH2:33]>O1CCOCC1>[Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:33][N:32]=2)[C:9]=1[F:25])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2cccnc2F)c1F
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncccc23)c1F

Procedure:
[4-[tert-butyl(dimethyl)silyl]-3,5,6-trifluoro-2-pyridyl]-(2-fluoro-3-pyridyl)methanone (159 g, 429.2 mmol) was dissolved in dioxane (1.6 L) and calcium carbonate (85.91 g, 858.4 mmol) was added. The reaction was in an ice bath and hydrazine hydrate (107.4 g, 104.4 mL, 2.146 mol) was added dropwise over 30 minutes. The resultant mixture was stirred overnight, after which time the thick suspension became a heterogeneous red solution. The reaction mixture was filtered through a pad of Celite, washing copiously with EtOAc/MeOH 7:1 (2×500 mL) and a small amount of water (100 mL). The filtrate was partitioned between EtOAc (1 L) and water (500 ml). The organic phase was washed with a sat aq NaHCO3 (500 mL). The combined aqueous layers were back-extracted with EtOAc (2×200 ml) and the combined organics were washed with brine (400 ml), dried over MgSO4 and filtered and concentrated to an orange solid. The solid was triturated with dichloromethane and filtered, washing with dichloromethane and petrol. This gave the title compound as an off-white solid. (103.8 g). The filtrate was concentrated under reduced pressure. The resulting solid was again triturated and filtered, washing with more petrol to give an off-white solid (36.7 g). The title compound was obtained as an off-white solid (total weight 140.5 g, 90%); 1H NMR (CDCl3) 0.55 (6H, s), 1.02 (9H, s), 7.21 (1H, m), 8.69 (1H, m), 8.91 (1H, s), 11.69 (1H, brs); MS ES (+) 365.18 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1C.F[C:21]1C=C([N+]([O-])=O)C=CC=1N1C[C@H](C)N[C@H](C)C1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][C@@H:13]([CH3:21])[N:14]([CH3:18])[C@@H:15]([CH3:17])[CH2:16]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)C[C@H](C)N1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)C[C@H](C)N1C
Yield: 100 %

Procedure:
Crude cis-4-(2-Fluoro-4-nitrophenyl)-1,2,6-trimethylpiperazine (6.1 g, 100% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine from 1-(2-fluoro-4-nitrophenyl)-cis-3,5-dimethylpiperazine (5.71 g, 24.2 mmol). LCMS-ESI (m/z): calcd for C13HBFN3O2, 267; [M+H]+ found, 268.
Reaction SMILES: Cl.[F:2][CH2:3][C@@:4]([C:12]([OH:14])=[O:13])([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].[CH:15]([O-])([O-])OC.[C:20]1([S:34]([OH:37])(=[O:36])=[O:35])[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30]([OH:33])(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([S:34]([OH:37])(=[O:36])=[O:35])[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30]([OH:33])(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][CH:21]=1.[F:2][CH2:3][C@@:4]([C:12]([O:14][CH3:15])=[O:13])([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5]
Reactant: N[C@@](CF)(Cc1c[nH]cn1)C(=O)O
Reactant: COC([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CO
Product: COC(=O)[C@](N)(CF)Cc1c[nH]cn1

Procedure:
Into a Fisher-Porter tube there was charged 5 g of (±) α-fluoromethylhistidine hydrochloride, 100 ml of methanol, 45 ml of methyl orthoformate and 9.7 g of naphthalene-1,5-disulfonic acid. The tube was sealed and heated in a steam bath overnight. The tube was cooled in an ice bath and the crystalline product (naphthalene-1,5 disulfonic acid salt of α-fluoromethylhistidine) was filtered and returned to the Fisher-Porter tube. Methanol (120 ml), methyl orthoformate (55 ml), and naphthalene-1,5 disulfonic acid (9.4 g) were added, the tube sealed and heated overnight in a steam bath, then cooled in an ice bath for ca. 5 hours. The crystals of (±)-methyl α-fluoromethylhistidinate 1,5-naphthalene disulfonate formed were filtered, washed with cold methanol and diethyl ether and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH2:17]1[C:25]2[C:20](=[CH:21][C:22]([N:26]=[C:27]=[O:28])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>C1COCC1.CO.C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:27]([NH:26][C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH2:19]4)=[O:28])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: NC(=O)c1c(-c2ccc(N)cc2)csc1N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)csc1N
Reaction time: 0.5 h

Procedure:
Crude 2-amino-4-(4-amino-phenyl)-thiophene-3-carboxylic acid amide (0.15 mmoles, 1 eq) is dissolved in 5 mL THF and treated with 400 μL of 0.35 M THF solution of 5-indanyl isocyanate (0.15 mmoles, 1 eq). When the reaction is complete, as judged by TLC analysis, the reaction mixture is diluted with 1 mL methanol and 1 mL triethylamine, stirred for 30 minutes, and concentrated to dryness. The residue is purified by prep HPLC yielding pure 2-amino-4-[4-(3-indan-5-yl-ureido)-phenyl]-thiophene-3-carboxylic acid amide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14]C)[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1>Br.C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[OH:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(O)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 89.8 %

Procedure:
The preparation comprises dissolving Ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.0 g, 30.9 mmol) in 40% HBr aqueous solution (20 mL) and acetic acid (20 mL) to react at 100° C., charging reaction mixture into ice water (500 mL) under fast stirring after the reaction finishes, going on with the stirring for 0.5 h, filtering, and drying obtained filter cake to give 1-cyclopropyl-6,7-difluoro-8-hydroxy-1,4-dihydro-oxoquinoline-3-carboxylic acid (7.8 g, 89.6%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH2:22][CH2:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:4])=[O:3].C1[C@@H]2CN(C3CCN(C4C=CC(N)=C(OC)C=4)CC3)CCN2CCO1>>[CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH2:22][CH2:23][CH3:24])[CH:14]=2)[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CCCc1cc(C2=CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC(N3CCN4CCOC[C@@H]4C3)CC2)ccc1N
Product: CCCc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1N
Yield: 74 %

Procedure:
The title compound of step D (0.249 g, 0.770 mmol, 74%) was prepared from 1-[2-(methylsulfonyl)ethyl]-4-(4-nitro-3-propylphenyl)-1,2,3,6-tetrahydropyridine in an analogous manner to that of 4-{4-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-1-piperidinyl}-2-(methyloxy)aniline (Example 87, step I). 1H NMR (400 MHz, CDCl3) δ ppm 1.00 (t, J=7.3 Hz, 3H), 1.61-1.71 (m, 4H), 1.83 (d, J=14.3 Hz, 2H), 2.14 (td, J=11.7, 2.2 Hz, 2H), 2.38 (dt, J=12.0, 3.7 Hz, 1H), 2.41-2.47 (m, 2H), 2.89 (t, J=6.4 Hz, 2H), 3.01 (d, J=11.4 Hz, 2H), 3.06 (s, 3H), 3.17 (t, J=6.4 Hz, 2H), 3.54 (br. s., 2H), 6.60-6.64 (m, 1H), 6.85-6.89 (m, 2H).