Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:4]=1.CCO>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C)CC2)ncc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.1 %

Procedure:
2-Chloro-4-methoxy-5-nitropyridine (Frontier Scientific, Newark, Del.; 1.02 g, 5.40 mmol) and K2CO3 (895 mg, 6.48 mmol) were purged with argon, treated with DMF (10 mL) followed by 1-methylpiperazine (0.66 mL, 5.94 mmol). The reaction mixture was then heated to 60° C. for 3 h. The reaction mixture was cooled to RT and treated with water, extracted with EtOAc (2×100 mL), washed with brine (2×25 mL) and dried over MgSO4, filtered and concentrated affording crude 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol, 99% yield). m/z (ESI, +ve ion) 252.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1H, s), 5.97 (1H, s), 3.97 (3H, s), 3.70-3.78 (4H, m), 2.47-2.55 (4H, m), 2.36 (3H, s). Pd/C (10 wt. %, 586 mg, 0.55 mmol) and 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol) were treated with EtOH (20 mL) and EtOAc (20 mL) and stirred at RT overnight (18 h) under an atmosphere of hydrogen (balloon). The reaction mixture was filtered through a pad of Celite, washed with MeOH, and concentrated to dryness affording 4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a) (1.22 g, 5.77 mmol, 99% yield) as a purple viscous oil. m/z (ESI, +ve ion) 223.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s), 6.17 (1H, s), 3.87 (3H, s), 3.37-3.45 (4H, m), 3.32 (2H, br. s.), 2.51-2.60 (4H, m), 2.36 (3H, s).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1.I[CH3:14].O>CN(C=O)C>[CH3:14][N:7]1[CH:8]=[C:4]([I:3])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cn1C
Reaction time: 2 h

Procedure:
780 mg (25.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 6.5 g (25.9 mmol) of methyl 4-iodo-2-pyrrolecarboxylate in 50 ml of DMF was added dropwise and stirring was carried out until gas evolution has ceased. 2.1 ml (33.6 mmol) of iodomethane were then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and was evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (40/60). 4.5 g (65%) of methyl N-methyl-4-iodo-2-pyrrolecarboxylate, with a melting point of 64°-65° C., were recovered.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:32]([O:34]C)=[O:33])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:36]([F:39])([F:38])[F:37])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:32]([OH:34])=[O:33])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:36]([F:37])([F:39])[F:38])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CCN1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1C(=O)O

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 269 under basic conditions (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 2.60-3.30 (m, 3H), 3.40-3.50 (m, 1H), 3.62 (d, J=12.0 Hz 1H),3.80 (m, 1H), 4.25-4.35 (m, 4H), 4.55 (m, 1H), 7.00 (s, 2H), 7.00-7.06 (m, 1H), 7.25 (m,2H), 7.5 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H). MS (APCI) m/z 553 (M+H)+. Calcd. Anal. C24H23F3N2O5.1.55 H2O: C, 54.35; H, 4.20; N, 5.07. Found: C, 54.16; H, 4.19; N, 4.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NCc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine and 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one, the title compound was prepared as a solid having a melting point of 243–244° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@:7]([OH:26])([CH:8]=[CH:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:25][C@@H:13]3[C:14]2=[O:24])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)C>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@:7]([OH:26])([CH:8]=[CH:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:25][C@@H:13]3[C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
A solution of 3β-acetoxy-5-hydroxy-15β,16β-methylene-5β-androst-6-en-17-one in 300 ml of methanol is stirred with 15 g of potassium carbonate for 30 minutes at room temperature. The reaction solution is diluted with diethyl ether, washed with water, dried, and evaporated, thus obtaining 27 g of 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one, mp 187°-190° C., (acetone).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccc(F)c(F)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccc(F)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3,4-difluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 26 ml DMF were added 1.172 ml benzyl bromoacetate and 4.607 g cesium carbonate. After stirring at RT for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[I:33]>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[I:33])[N:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2[nH]ncc2cc1SCc1ccccc1
Reactant: BrCc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Fc1cc2c(cnn2Cc2ccccc2I)cc1SCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-(benzylthio)-6-fluoro-1H-indazole (1-2, 1.5 g, 5.81 mmol, 1.0 equiv) in NMP (29.0 mL) was added cesium carbonate (5.68 g, 17.42 mmol, 3.0 equiv) and 1-(bromomethyl)-2-iodobenzene (2.59 g, 8.71 mmol, 1.5 equiv) and the reaction mixture was stirred at ambient temperature. Upon completion, the reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography followed by reverse phase chromatography (50%→100% 0.1% TFA in ACN: 0.1% TFA in water) to yield the desired regioisomer. ESI+ MS [M+H]+ C21H16FIN2S: 475.1 found, 475.3 required.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[N:17]=1.O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:17]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1COc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.6 g or 4-t-butylphenol in 10 ml of DMF at 0° C., was added portionwise 0.13 g of 60% sodium hydride, and stirred at room temperature for 1 hour. 1.0 g of 5-chloromethyl-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4 triazole was added to the solution at 0° C., and stirred at room temperature overnight. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 1.3 g of 5-(4-t-butylphenoxymethyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole. m.p.84°-86° C.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(C4C=CC([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:65])[CH:48]([C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[NH:49][C:50](=[O:58])[CH2:51][CH:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)=[N:40][CH:41]=5)=CC=4)C=3)C=2)=CN=1)=O)C(C)C.[CH3:67][O:68][C:69](=[O:125])[NH:70][CH:71]([C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]1[NH:86][C:85]2[C:87]3[C:92]([CH2:93][CH2:94][C:84]=2[N:83]=1)=[CH:91][C:90]([C:95]1[CH:104]=[CH:103][C:102]2[C:97](=[CH:98][CH:99]=[C:100](C4NC(C5CCCN5C(=O)C(N)C5C=CC=CC=5)=NC=4)[CH:101]=2)[CH:96]=1)=[CH:89][CH:88]=3)=[O:76])[CH:72]([CH3:74])[CH3:73]>>[CH3:67][O:68][C:69](=[O:125])[NH:70][CH:71]([C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]1[NH:86][C:85]2[C:87]3[C:92]([CH2:93][CH2:94][C:84]=2[N:83]=1)=[CH:91][C:90]([C:95]1[CH:104]=[CH:103][C:102]2[C:97](=[CH:98][CH:99]=[C:100]([C:37]4[NH:38][C:39]([CH:42]5[CH2:46][CH2:45][CH2:44][N:43]5[C:47](=[O:65])[CH:48]([C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[NH:49][C:50](=[O:58])[CH2:51][CH:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:40][CH:41]=4)[CH:101]=2)[CH:96]=1)=[CH:89][CH:88]=3)=[O:76])[CH:72]([CH3:74])[CH3:73]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C(C)C
Yield: 15 %

Procedure:
This compound was prepared using the same procedure used to make {2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester using (1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.020 g, 0.022 mmol) to give [2-Methyl-1-(2-{7-[6-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.003 g, 15% yield). LCMS-ESI+: calc'd for C54H60N8O6: 916.46 (M+); Found: 917.44 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:35])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:15]4[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]5[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=5[F:34])[C:16]=4[N:17]=[C:18](SC)[N:19]=3)[CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6](=[O:35])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:15]4[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]5[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=5[F:33])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(-c2cc(C(=O)NCC3CC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ncnc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.3 %

Procedure:
N-(cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide (13.5 mg, 0.027 mmol), was dissolved in anhydrous methanol (2 mL) and was added to a tube containing nickel chloride hexahydrate (2 mg). The tube was placed under an atmosphere of nitrogen and cooled using a dry-ice/acetone bath to about −15° C. Sodium borohydride (2 mg) was then added (nitrogen removed during addition and then replaced) and the solution turned black. The solution was stirred in the dry ice/acetone bath for 1.5 h. 1 N HCl (4 mL) was added and the solution was allowed to warm to room temperature and stirred under an air atmosphere for about 2 hours. Dichloromethane (2 mL) was added to the solution and it was stirred vigorously for 10 min. The solution was filtered through a hydrophobic frit packed with celite and was washed with further dichloromethane (2 mL×2). The filtrate was concentrated and purified by HPLC to give the title product (1 mg, 8.2%). LC-MS m/z 447 (M+H)+, 2.98 min (ret time). 1H-NMR (d6-DMSO) δ 0.22 (m, 2H), 0.42 (m, 2H), 1.01 (br s, 1H), 2.23 (s, 3H), 3.14 (br s, 2H), 6.87 (m, 1H), 7.43 (m, 2H), 7.65 (m, 2H), 7.95 (m, 2H), 8.60 (m, 1H), 9.07 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>O.O1CCOCC1>[Cl:11][C:12]1[N:13]=[CH:14][N:15]=[C:16]([NH:1][CH2:2][C@@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[CH:17]=1
Reactant: NC[C@H](O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccccc1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a solution consisting of (R)-(−)-2-amino-1-phenylethanol (4.80 g, 35.0 mmol) in and 1,4-dioxane (150 mL) at rt was added dropwise a solution consisting of 4,6-dichloropyrimidine (5.21 g, 35.0 mmol) and 1,4-dioxane (75 mL). Upon complete addition, NaHCO3 (17.6 g, 0.210 mol) was added and the mixture was heated to reflux (100° C.) for 17 h. The reaction mixture was cooled, diluted with water (60 mL) and the pH was adjusted to 12 by the addition of a 1 N NaOH (25 mL). The solution was extracted with CH2Cl2 (75 mL), washed with satd. aq. NaCl (50 mL), and the organic extract was dried (Na2SO4) and concentrated. The crude material (8.2 g) was suspended in CH2Cl2 (40 mL) and warmed to 50° C. to give a homogeneous solution. The solution was cooled to rt and treated with a few drops of hexanes to give the title compound as a pale yellow solid (7.0 g, 81%). MS (ESI): mass calcd. for C21H20F3N3O2, 403.2; m/z found, 404.2 [M+H]+. 1H NMR (CD3OD): 8.44 (s, 1H), 8.15 (s, 1H), 8.09 (dd, J=8.8, 2.2 Hz, 1H), 7.43 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.27-7.25 (m, 2H), 6.86 (s, 1H), 4.91-4.88 (m, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.76-3.68 (m, 1H), 3.58 (dd, J=13.7, 7.7 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[C:13]([CH3:14])=[CH:12][S:11][C:10]=13)[NH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5]2>[OH-].[Na+].CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[C:13]([CH3:14])=[CH:12][S:11][C:10]=13)[NH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Br)c3scc(C)c3c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1csc2c(Br)cc3cc(C(=O)O)[nH]c3c12
Temperature: 25 °C
Yield: 100.3 %

Procedure:
2.5 g of (70) was hydrolyzed during 3 hours at reflux in a mixture of 25 ml 4 N NaOH and 100 ml MeOH/water 1+1. After cooling to room temperature and acidification with acetic acid the product precipitated. Filtration and drying gave 2.4 g of (71). M.p. 229°-41° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:26]=[O:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][OH:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 780 mg (2.08 mmol) of 1-benzyl-7-(4-fluorobenzyloxy) 3-formyl-2 -methylpyrrolo [2,3-d]pyridazine in 50 ml of ethanol is treated with 80 mg (2.1 mmol) of sodium borohydride and stirred at room temperature for 30 min. After addition of 100 ml of water, the mixture is concentrated on a rotary evaporator to half the volume. The precipitate is filtered off, washed with 50 ml of water and dried in a high vacuum over potassium hydroxide. 670 mg (85%) of the title compound are isolated. M.p.: 122°-124° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:33]([O-:35])=[O:34])=[C:6]([CH:32]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:20][CH:19]=2)[CH:15]=1)=[O:8].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH3:31][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:32]=[C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:3]=[CH:4][C:5]=2[N+:33]([O-:35])=[O:34])=[CH:15][C:14]=1[NH:16][C:17](=[O:30])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])ccc2C)cc1
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(N4CCOCC4)ccc3[N+](=O)[O-])ccc2C)cc1
Temperature: 100 °C
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 105° C. for 16 hours rather than to 100° C. for 6 days, N-[5-(5-chloro-2-nitrobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with morpholine. The solid so obtained was dissolved in methylene chloride and the solution was washed with a saturated aqueous sodium bicarbonate solution. The organic solution was dried (MgSO4) and evaporated. There was thus obtained the title compound in 64% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 2.2 (s, 3H), 2.4-2.6 (m, 4H), 3.4-3.5 (m, 4H), 3.6 (s, 2H), 3.7-3.8 (m, 4H), 7.0-7.1 (m, 2H), 7.2 (m, 1H), 7.4-7.5 (m, 2H), 7.7 (m, 1H), 7.9 (d, 2H), 8.05 (d, 1H), 9.85 (s, 1H), 10.38 (broad s, 1H); Mass Spectrum: M+H+546.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][CH3:43])[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:27]([F:28])([F:30])[F:29])[N:8]=[CH:9]4)[C:18](=[O:24])[N:19]=2)[CH3:43])[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCOC(=O)N1CCC(NC)CC1
Product: CCOC(=O)N1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-piperidine-1-carboxylic acid ethyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and 4-methylamino-piperidine-1-carboxylic acid ethyl ester following General Procedure B.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C@@H:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:14]2)=[CH:9][CH:8]=1)C.CO.[Li+].[OH-]>O>[C:21]1([C@H:19]([NH:18][C@H:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:12][CH:11]=3)[CH2:14]2)[CH3:20])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid ethyl ester (0.214 g, 0.51 mmol) was added to a mixture of methanol (2.35 ml) and water (0.78 ml). To the milk-white mixture was added aqueous 2N LiOH (2.05 ml, 4.1 mmol). After stirring for about 10 minutes at room temperature the reaction mixture changed into a clear light yellow solution. The solution was stirred overnight at room temperature. After 20 hours the solution was concentrated slightly in vacuo and further 5 ml of water was added. The product was precipitated by adding 4N HCl (2.4 ml) under vigorous stirring. pH was adjusted to 5 with aqueous 2N LiOH. The precipitate was collected by filtration to give crude amorphous {4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]phenoxy}-acetic acid. Yield: 0.19 g (95%).
Reaction SMILES: [C:1](/[C:3](/[CH:13]=[CH2:14])=[CH:4]\[C@@H:5]1[C@@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2].S(Cl)([Cl:17])=O>O1CCCC1.CN(C)C=O>[C:1](/[C:3](/[CH:13]=[CH2:14])=[CH:4]\[C@@H:5]1[C@@H:7]([C:8]([Cl:17])=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2]
Reactant: C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
(1R)-trans-3-[(1Z)-2-cyano-1,3-butadienyl]-2,2-dimethylcyclopropanecarboxylic acid (440 mg, 2.30 mmol) was dissolved in 3 mL of tetrahydrofuran and then thionyl chloride (301 mg, 2.53 mmol) and 10 mg of N,N-dimethylformamide were added and the solution was stirred at room temperature for 1 hours, and further at 60° C. of 3 hours. The reaction solution was concentrated under reduced pressure condition to obtain 460 mg of (1R)-trans-3-[(1Z)-2-cyano-1,3-butadienyl]-2,2-dimethylcyclopropanecarboxylic acid chloride represented by the following formula: