Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(C)C>Cl>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][CH2:10][CH2:9][CH:8]([NH2:7])[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)NC(CCCc1cccnc1)CCCc1cccnc1
Agent: Cl
Product: NC(CCCc1cccnc1)CCCc1cccnc1
Yield: 80 %

Procedure:
As in Example 37, hydrolysis of 5.4 g of [1-[3-(3-pyridinyl)-propyl)-4-(3-pyridinyl)butyl]carbamic acid 1,1-dimethylethyl ester in 55 mL of 1N HCl yielded 3.15 g of alpha-[3-(3-pyridinyl)propyl]-3-pyridinebutanamine.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][OH:9])=[CH:4][CH:3]=1.[CH3:10][N:11]=[C:12]=[O:13]>>[OH:9][N:8]([CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]([NH:11][CH3:10])=[O:13]
Reactant: ONCc1ccc(Br)s1
Reactant: CN=C=O
Product: CNC(=O)N(O)Cc1ccc(Br)s1

Procedure:
The title compound is prepared from (5-bromothien-2-yl)methyl hydroxylamine from Example 127 by reaction with methyl isocyanate instead of trimethylsilylisocyanate.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)=[O:30]>>[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:30])[CH2:20][CH2:19]2)[CH:13]=1)=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-methylphenyl)-1-butanone: ESMS m/e: 407.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH2:16]O)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:12][C@H:11]2[CH3:26])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:41]1[CH:45]=[N:44][N:43]=[N:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@@H:14]([CH2:16][C:45]3[NH:44][N:43]=[N:42][N:41]=3)[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][C@H:11]2[CH3:26])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1C(=O)COc1ccc(Cl)cc1
Reactant: c1nnn[nH]1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@H](Cc2nnn[nH]2)CN1C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 13 %

Procedure:
To a solution of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((hydroxy)methyl)piperazine (0.17 g, 0.42 mmol) in CH2Cl2 (50 mL) at 0° C. was added triethylamine (excess) and methane sulfonyl chloride (0.050 mL, 0.5 mmol). The resultant mixture was stirred at 0° C. until consumption of alcohol was observed by TLC analysis. The mixture was concentrated of volatiles in vacuo. Residue was taken up in anhydrous DMF (5 mL) and K2CO3 (excess) added, followed by tetrazole (0.050 g, 0.71 mmol). The resulting mixture was stirred at ambient temperature for 3 days and filtered. The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate. This was washed with water then brine, then dried over MgSO4 and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 25 mg of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((tetrazolyl)methyl)piperazine as a white solid: NMR (CDCl3) 7.3 (m, 5), 7.0 (m, 4), 4.84.1 (m, 5), 3.8 (m, 3), 3.2 (m, 2), 2.8 (dd, 1), 2.5 (dd, 1), 1.4 (d, 3) ppm, MS (ESI) 458.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:21]1(=[O:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22]1>>[O:26]=[C:24]1[CH2:23][CH2:22][C:21](=[O:27])[N:25]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCN2C(=O)CCC2=O)cc1)c1ccccc1
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield as crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and succinimide. 1H NMR (400 MHz; CDCl3): δ 2.65 (s, 4H), 2.86 (t, 2H), 3.41 (br s, 3H), 3.72 (t, 2H), 7.04 (br d, 2H), 7.19 (d, 2H), 7.26–7.42 (m, 5H); HPLC-MS: m/z=353.2 (M+1); Rt=3.17 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:4][CH2:3]1.[CH2:16]([O:23][C:24](=[O:33])[NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+].C1COCC1>CO.C(O)(=O)C>[CH2:16]([O:23][C:24](=[O:33])[NH:25][CH2:26][CH:27]1[CH2:28][CH2:29][N:30]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])[CH2:4][CH2:3]2)[CH2:31][CH2:32]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccccc1N1CCC(=O)CC1
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCC(N2CCC(CNC(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(4-oxo-piperidin-1-yl)-benzonitrile (5) (653 mg, 3.26 mmol) and 4 (890 mg, 3.58 mmol) in 40 ml of methanol was added 4 g of powdered 4 Å molecular sieves. The resulting suspension was stirred at room temperature for 24 hours. The suspension was subsequently acidified to pH 5 with acetic acid and a 1M solution of NaCNBH3 in THF (6.0 ml 5.6 mmol) was added slowly with a syringe pump over 24 hours. When the addition was complete, the solvent was removed in vacuo and the residue taken up in chloroform and filtered. The solution was then washed with 10% Na2CO3, dried over MgSO4, and the solvent removed in vacuo to give the crude amine. The crude product was purified by chromatography on silica gel (5% MeOH/CHCl3) to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([CH2:12][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH3:15])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[Br:22].N1C=CC=CC=1.[OH-].[Na+].[CH2:31]([OH:34])[CH2:32][OH:33]>O>[NH2:2][C:3]1[C:11]([CH2:12][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([O:33][CH2:32][CH2:31][OH:34])=[O:8])=[CH:5][C:4]=1[Br:22]
Reactant: CCN(Cc1cc(C(=O)Cl)cc(Br)c1N)C1CCCCC1
Reactant: OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN(Cc1cc(C(=O)OCCO)cc(Br)c1N)C1CCCCC1
Temperature: 105 °C

Procedure:
41 gm (0.1 mol) of 4-amino-3-bromo-5-(N-ethylcyclohexylaminomethyl)-benzoyl chloride hydrochloride were dissolved in 250 ml of ethylene glycol, and after addition of 17 gm (0.22 mol) of pyridine the solution was heated to 105° C. for one hour. After cooling to room temperature, the mixture was diluted with 1 liter of water. After addition of aqueous sodium hydroxide the mixture was extracted with ether, the ether extract was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silicagel (eluant: ethyl acetate). After evaporation of the eluate, a resin was obtained which was converted into crystals by trituration with petroleum ether. The crystals obtained were recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH2:16][O:17][CH3:18].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH2:16][O:17][CH3:18])=[O:19]
Reactant: OB(O)c1ccccc1
Reactant: COCOc1cc(OCOC)c(C(=O)OC)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: COCOc1cc(OCOC)c(-c2ccccc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
A Schlenk tube was charged with 5-bromo-2,4-bis-methoxymethoxy-benzoic acid methyl ester (3) (503 mg, 1.5 mmol), penylboronic acid (272 mg, 2.3 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (82 mg, 0.2 mmol), K3PO4 H2O (4.70 g, 34.0 mmol). The reaction tube was evacuated and backfilled with N2 (X3). Toluene (10 mL, anhydrous and sure seal bottle from Aldrich) was added. The reaction was stirred at room temperature for 10 min and heated at 105° C. (preheated oil bath) for 24 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL) and water (70 mL). The aqueous phase was extracted with EtOAc (40 mL×3) and the combined organic layers were washed with water and brine and dried over MgSO4. The purification of the concentrated crude product by column chromatography (25% EtOAc in Hexane) afforded the title product as colorless oil (460 mg, 93%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]4[CH2:26][CH:25]5[C:27]6([CH2:31][N:30]([CH2:32][C:33]([F:36])([F:35])[F:34])[S:29](=[O:38])(=[O:37])[NH:28]6)[CH:22]([CH2:23][CH2:24]5)[CH2:21][C:20]=4[CH:39]=3)=[N:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[F:41][C:2]([F:1])([F:40])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]4[CH2:26][CH:25]5[C:27]6([CH2:31][N:30]([CH2:32][C:33]([F:36])([F:35])[F:34])[S:29](=[O:37])(=[O:38])[NH:28]6)[CH:22]([CH2:23][CH2:24]5)[CH2:21][C:20]=4[CH:39]=3)=[N:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: O=C(N1CC=C(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N1CCC(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1)C(F)(F)F
Yield: 99.7 %

Procedure:
A mixture of the tetrahydropyridine from Example 41 (0.018 g, 0.029 mmol), palladium on carbon (0.01 g) and ethyl acetate (2 mL) was stirred under 1 atmosphere of hydrogen for 16 hours. The catalyst was removed by filtration through a glass fibre pad and the solvent removed in vacuo to give the title compound (0.018 g, quant.).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[F:28])[CH:12]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:30][NH2:31]>C(O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([F:28])=[C:21]([C:13]2[CH:12]=[C:11]([NH:10][C:9]3[C:4]([C:3]([NH:31][CH3:30])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:26]=1
Reactant: COC(=O)c1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Reaction time: 16 h

Procedure:
14.4 mg 4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-nicotinic acid methyl ester were treated with 250 μl of 33% methylamine in ethanol at 40° C. for 5 min and then at ambient temperature for 16 hrs. After evaporation the product was digerated with ether and dried to give 15.7 mg 4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-N-methyl-nicotinamide as a yellowish powder with Rt˜1.47 min and correct mass M+H˜408.
Reaction SMILES: O1C2C(=CC=CC=2)[C@H](NC([C@@H]2CC3C(=CC([C@H]4C[C@@H](C(=O)N[C@H]5C6C(=CC=CC=6)CCC5)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C4)=CC=3)CN2C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)=O)CC1.C(O[C:75]([N:77](C)[C@@H:78]([CH3:152])[C:79]([NH:81][C@@H:82]([C:148]([CH3:151])([CH3:150])[CH3:149])[C:83]([N:85]1[CH2:89][C@@H:88]([C:90]2[CH:99]=[C:98]3[C:93]([CH2:94][C@@H:95]([C:121](=[O:133])[NH:122][C@H:123]4[C:132]5[C:127](=[CH:128][CH:129]=[CH:130][CH:131]=5)[CH2:126][CH2:125][CH2:124]4)[N:96]([C:100](=[O:120])[C@@H:101]([NH:106][C:107](=[O:119])[C@@H:108]([N:110](C(OC(C)(C)C)=O)[CH3:111])[CH3:109])[C:102]([CH3:105])([CH3:104])[CH3:103])[CH2:97]3)=[CH:92][CH:91]=2)[CH2:87][C@H:86]1[C:134](N[C@@H](CC1C=CC=CC=1)C(O)=O)=[O:135])=[O:84])=[O:80])=O)(C)(C)C.[CH3:154][C:155]1[O:159][C:158]([C@@H:160]([NH2:168])[CH2:161][C:162]2[CH:167]=[CH:166][CH:165]=[CH:164][CH:163]=2)=[N:157][N:156]=1>>[CH3:105][C:102]([CH3:103])([CH3:104])[C@H:101]([NH:106][C:107](=[O:119])[C@@H:108]([NH:110][CH3:111])[CH3:109])[C:100]([N:96]1[C@H:95]([C:121]([NH:122][C@H:123]2[C:132]3[C:127](=[CH:128][CH:129]=[CH:130][CH:131]=3)[CH2:126][CH2:125][CH2:124]2)=[O:133])[CH2:94][C:93]2[C:98](=[CH:99][C:90]([C@H:88]3[CH2:87][C@@H:86]([C:134](=[O:135])[NH:168][C@H:160]([C:158]4[O:159][C:155]([CH3:154])=[N:156][N:157]=4)[CH2:161][C:162]4[CH:167]=[CH:166][CH:165]=[CH:164][CH:163]=4)[N:85]([C:83](=[O:84])[C@@H:82]([NH:81][C:79](=[O:80])[C@@H:78]([NH:77][CH3:75])[CH3:152])[C:148]([CH3:149])([CH3:150])[CH3:151])[CH2:89]3)=[CH:91][CH:92]=2)[CH2:97]1)=[O:120]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1nnc([C@@H](N)Cc2ccccc2)o1
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)c1nnc(C)o1)C(C)(C)C
Yield: 53 %

Procedure:
Following procedures analogous to those for the preparation of Compounds F and G of Example 46, (S)-2-((2S,4R)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidine-2-carboxamido)-3-phenylpropanoic acid (Compound D of Example 46, 50 mg, 0.049 mmol) and (S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-phenylethanamine (10 mg, 0.049 mmol) were converted to the title compound (26 mg, 53% over 2 steps). MS (ESI+) m/z 1001.8 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:1]([NH:17][C@H:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: C[C@@H](NCc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred solution of benzaldehyde (1.58 mL, 15.5 mmol) in 10 mL of absolute ethanol at room temperature under nitrogen was added (R)-α-methylbenzylamine (2.0 mL, 15.51 mmol, 99% ee.). The reaction mixture was stirred for 3 hours. The reaction solution was then dried over magnesium sulfate and diluted to a 60 mL volume with EtOH, Ethanol washed Raney nickel Ni (~1.5 g) was added and the resulting suspension was treated with 58 psi of hydrogen in a Parr Type Shaker. After 1 day, additional Raney nickel (~1 g) and 30 mL of ethanol were added and the hydrogenolysis continued for 3 days. The reaction mixture was filtered through Celite to remove the catalyst and concentrated to afford 3.11 g (95%) of N-benzyl (R)-α-methylbenzylamine as a pale yellow oil contaminated with ~5% of benzyl alcohol and (R)-α-methylbenzylamine; 1H NMR (DMSO-d6, 250 MHz)δ 7.1-7.5 (m, 10H, Ar), 3.68 (q, 1H, J=6.6 Hz), 3.48 (dd, 2H, J=13.6 Hz, J2=20.5 Hz), 1.26 (d, 3H, J=6.6 Hz, CH3); 13C NMR (DMSO-d6)δ 146.1, 141.0, 128.2, 128.0, 127.8, 126.5, 126.4, 56.7, 50.6, 24.5. This mixture was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:38](=O)[CH3:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:42][OH:43].C(O)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34](/[C:38](=[N:42]/[OH:43])/[CH3:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 50 °C
Yield: 67.5 %

Procedure:
To a mixture of 1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone (0.10 g, 0.168 mmol) and hydroxylamine hydrochloride (0.0125 g, 0.188 mmoL) in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixture was heated at 50° C. for 3 hours. After cooled to room temperature, the mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL×3), water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.069 g (67%) of the title compound as an off-white solid. M.p.=156-158° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 11.08 (s, 1H), 8.70 (br. s, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.87 (s, 1H), 7.77-7.74 (m, 2H), 7.71-7.59 (m, 3H), 7.59-7.56 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.48-2.45 (m, 1H), 2.33 (t, J=7.6 Hz, 1H), 2.15 (s, 3H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.34 (m, 1H); LCMS: 608 [M+H].
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1CC(=O)CC[C@@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nccc1[C@H]1C[C@@H](O)CC[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
To a solution of the (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)-4-oxocyclohexyl benzoate (430 mg, 1.44 mmol) prepared in Example 162c in ethanol (7.0 mL), sodium borohydride (164 mg, 4.34 mmol) was added, and the mixture was stirred at room temperature for 5 hours. To the reaction solution, water (10 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with reverse phase chromatography (YMC HPLC COLUMN, YMC-Pack ODS-A; methanol/water=6:4) to yield the title compound (293 mg, 69%) as a colorless solid.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11](Br)[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C=O.[CH:39]#[N:40]>CC(N(C)C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn].[C].[Pd].O>[N:1]1([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:39]#[N:40])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C#N
Reactant: O=C(NN1CCOCC1)c1ccc(O)c(Br)c1
Agent: [Pd]
Agent: C=O
Agent: [C-]#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(C(=O)NN2CCOCC2)ccc1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
3-Bromo-4-hydroxybenzoic acid (4-morpholinyl)amide (150 g, 0.524 mol), zinc cyanide (44.23 g, 0.341 mmol), zinc (0.90 g, 14 mmol) and 5% palladium-carbon (44.6 g, 0.021 mmol) are suspended in dimethylacetamide (1500 mL), and bubbled with nitrogen for 35 minutes. After further adding triphenylphosphine (22.0 g, 0.084 mmol) under nitrogen, the reaction mixture is heated at 120° C., and stirred for 4 hours. The mixture is cooled to 25° C., stirred overnight, and the insoluble materials are separated by filtration at room temperature. The active carbon is washed with dimethylacetamide (1V, 150 mL). In the following procedures, an aliquot is used, which is obtained by dividing the solution above equally into five aliquots. The solvent is evaporated so that 2V of dimethylacetamide remains. After adding toluene (180 mL 6V), conc. hydrochloric acid (0.71 w, 21.3 g) is added dropwise at 30° C. or below and bubbled with nitrogen at 25° C. for one hour. Toluene is evaporated until the concentration of hydrogen cyanide becomes 50 ppm or less (20 mmHg). After adding water (5.4V, 163 mL), 37% formalin (17 mL, 2 equiv.) is added at room temperature. The mixture is stirred overnight, and the amount of hydrogen cyanide in the gas phase is confirmed to be 5 ppm on a detection tube. After adding 37% formalin (17 mL, 2 equiv.), the mixture is stirred at 35° C. for one hour, and the amount of hydrogen cyanide in the gas phase is confirmed to be 1 ppm or below on a detection tube. The mixture is ice-cooled (4° C.) for one hour. The crystals are collected by filtration, washed with water (6V, 180 mL), aqueous 5% sodium bicarbonate (1V, 30 ml), and then water (2 v, 60 ml) (pH=7). The wet materials are suspended into acetone (1.5 V, 45 mL), stirred for 0.5 hours under reflux, cooled gradually, stirred at 5° C. for one hour under ice-cooling, and filtered. The resulting crystals are washed with 0.5V of acetone (15 mL), and dried with a conical dryer to give 3-cyano-4-hydroxybenzoic acid (4-morpholinyl)amide (20.06 g, yield: 82.4%, content: 98.1%). Mp: 238-240° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:25].[K+].[K+]>Cl>[C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](=[O:25])[NH:18][N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(=O)[nH]n1
Reaction time: 2 h

Procedure:
A stirred solution of 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl-6-chloropyridazine (10.0 g, 0.03 mol) in 18% hydrochloric acid (60 ml) was heated under reflux for 8 hours. Potassium carbonate was added to the cold solution to take it to pH 10, and after allowing the mixture to stand for 2 hours the solid was collected by filtration and washed with water to give a crude hydrate (10.35 g). Recrystallisation from ethyl acetate gave 6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone (7.42 g) as a colourless solid, m.p. 161.5°-163.5° C.