Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C#CCC.[Li][CH2:6][CH2:7][CH2:8][CH3:9].Cl[C:11]1([C:24]([F:27])([F:26])[F:25])[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:23])[O:12]1>C1COCC1>[C:6]([C:11]1([C:24]([F:26])([F:27])[F:25])[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:23])[O:12]1)#[C:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: COc1ccc2c(c1)C(Cl)(C(F)(F)F)OC(=O)N2
Agent: C#CCC
Solvent: C1CCOC1
Product: CCC#CC1(C(F)(F)F)OC(=O)Nc2ccc(OC)cc21
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
To a stirred, cooled(−78° C.) solution of 0.5 g(excess) of 1-butyne in 3 mL of anhydrous THF was added 1.6 mL(4.0 mmol) of a 2.5M solution of n-BuLi in hexanes over 3 min. The solution was stirred 5 min. and charged with 266 mg(1.00 mmol) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a single portion. The solution was warmed to −10° C. over 20 min., whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO3 then brine. The solution was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexanes to afford 144 mg(48%) of 4-(1-butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 161-162° C. 1H NMR(300 MHz, CDCl3) δ8.81(br. s, 1H); 7.07(d, 1H, J=2 Hz); 6.94(dd, 1H, J=9, 2 Hz); 6.81(d, 1H, J=8 Hz); 3.82(s, 3H); 2.34(q, 2H, J=7 Hz); 1.22(t, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH2:29][OH:30])[CH:17]=[C:18]([C:20]3[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=3)[N:19]=2)=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3[N:16]([CH2:28][CH2:29][O:30][C:11]=2[CH:10]=1)[CH:17]=[C:18]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:19]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1ncnc1-c1cn(CCO)c(-c2ccc(OCc3ccccc3)cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OCc3ccccc3)cc1OCC2
Yield: 58.4 %

Procedure:
A solution of 2-[2-(4-benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (25.0 g, 59.31 mmol) in DMF (890 mL) was treated with sodium hydride (3.51 g, 94.89 mmol) by portionwise addition. The resultant mixture was stirred for 23 h at RT and quenched with ice and H2O. The precipitate was collected by filtration, washed with H2O and dried in vacuo at 60° C. to give 8-Benzyloxy-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as an off-white solid (13.9 g, 58%). 1H NMR (400 MHz, CDCl3): 8.43 (1H, d, J=8.97 Hz), 7.87 (1H, s), 7.63 (1H, s), 7.41-7.39 (5H, m), 6.82 (1H, dd, J=8.98, 2.58 Hz), 6.64 (1H, d, J=2.55 Hz), 6.00 (1H, m), 5.10 (2H, s), 4.50-4.48 (2H, m), 4.42-4.41 (2H, m), 1.59 (6H, d, J=6.63 Hz). LCMS: RT=3.80 min, [M+H]+=402.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:26])[NH:44][CH:41]5[CH2:43][CH2:42]5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C(O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)NC1CC1
Yield: 39.9 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (250 mg), 1,1′-carbonyldiimidazole (130 mg) and cyclopropylamine (45 mg) were treated as in Example 151 to give the title compound (110 mg) as a white powder (yield: 40%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26](/[C:29](=[N:31]\[S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])/[CH3:30])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][S:32]([C:34]([CH3:36])([CH3:35])[CH3:37])=[O:33])([CH3:30])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1ccc(/C(C)=N\S(=O)C(C)(C)C)cc1
Reactant: COC(C)=O
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCOc1ccc(C(C)(CC(=O)OC)NS(=O)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
To a stirred solution of diisopropylamine (3.86 mL, 27.1 mmol) in THF (40 mL) at −78° C. was added n-butyllithium (22.57 mL, 27.1 mmol) dropwise. The reaction was slowly warmed up to −20° C. and stirred for 45 min. The reaction was cooled to −78° C. and methyl acetate (2.006 g, 27.1 mmol) was added dropwise. After 30 min, chlorotitanium triisopropoxide (8.09 mL, 33.8 mmol) in THF (40 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h. Intermediate 107A (4 g, 13.54 mmol) in THF (15 mL) was added dropwise and the reaction was stirred at −78° C. for 2 h. The reaction was quenched by addition of sat'd NH4Cl solution and stirred vigorously while warmed to rt. The mixture was filtered through Celite® and washed with EtOAc. The filtrate was washed with H2O, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (4.33 g, 87%) as a light yellow oil. LCMS Anal. Calc'd for C19H31NO4S 369.20, found [M+H] 370.2. 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=8.80 Hz, 2H), 6.85 (d, J=8.80 Hz, 2H), 3.95 (t, J=6.46 Hz, 2H), 3.62 (s, 3H), 2.05 (s, 2H), 1.74-1.80 (m, 2H), 1.74 (s, 3H), 1.44-1.54 (m, 2H), 1.29 (s, 9H), 0.98 (t, J=7.43 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:30])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[NH2:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:23][C:22]([C:24]3[N:28]=[C:27]([CH3:29])[O:26][N:25]=3)([CH3:30])[CH3:21])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCc3ccccn3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=394.2 [M+H]+.
Reaction SMILES: CO.[F:3][C:4]1[C:11]([F:12])=[C:10]([CH2:13]Br)[C:9]([F:15])=[C:8]([F:16])[C:5]=1[CH2:6][OH:7]>[Pd].O>[F:3][C:4]1[C:11]([F:12])=[C:10]([CH3:13])[C:9]([F:15])=[C:8]([F:16])[C:5]=1[CH2:6][OH:7]
Reactant: OCc1c(F)c(F)c(CBr)c(F)c1F
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1c(F)c(F)c(CO)c(F)c1F
Yield: 89.3 %

Procedure:
The following procedures were carried out in a 1 litre glass autoclave (working volume 350-500 mls) fitted with a dispersion agitator (1000 rpm). H2 gas was fed through a dip-pipe via a Buchi gas controller (Type 6002). The increase/decrease of the temperature is controlled by a Jelabo FP40 external heating/cooling bath. Methanol (362 g, water (6 g, 2,3,5,6-tetrafluoro-4-(bromomethyl)benzyl alcohol (95.1 g 100% wt.), MgO (18.1 g and 5% palladium/carbon catalyst (0.8 g, 100 wt %; Type 58, provided by Johnson Matthey) were charged to the autoclave. The lid was sealed and the autoclave was initially purged with nitrogen to remove residual oxygen (nearly 0), then pressurized to 2.5 bar with hydrogen, and stirred. The pressure was maintained at 2.5 bar by the Buchi controller. The reaction temperature was controlled at 50° C. throughout the reaction by means of the external heating/cooling bath. The reaction was continued until the consumption of hydrogen ceased (typically 60 to 90 minutes). The residual pressure was released and the autoclave purged with nitrogen. The contents of the autoclave were discharged, followed by a small methanol (30 g wash. The spent catalyst and inorganic salts were removed and recovered by filtration. The filter cake was washed with a small amount of methanol (2×30 g. The filtrates and filter-cake washes were combined. On analysis, the reaction had produced 60.4 g of 2,3,5,6-tetrafluoro-4-methylbenzyl alcohol with a yield of 89.4%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@H]1CN(Cc2ccccc2)C[C@@H]1OCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound VI-10 (966 mg, 54.1%) was obtained in the same manner as that in Reference Example 1, by using (3S,4S)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 500 mg, 2.59 mmol) and (9Z,12Z)-octadec-9,12-dienyl methanesulfonate (Nu-Chek Prep, Inc; 2.23 g, 6.47 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[S:12]1[CH2:16][C:15](=S)[NH:14][C:13]1=[O:18]>CO>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:15]1[CH2:16][S:12][C:13](=[O:18])[N:14]=1
Reactant: O=C1NC(=S)CS1
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CO
Product: Cc1nc[nH]c1CSCCNC1=NC(=O)SC1
Yield: 37 %

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.71 g.) and thiazolidine-2-one-4-thione (1.33 g.) in methanol (30 ml.) was heated under reflux for one hour. Concentration, followed by successive recrystallisation of the residue from methanol, ethanol and aqueous ethanol afforded 4-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]thiazoline-2-one (1.0 g.) m.p. 195°-197°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of nickel(II) chloride hexahydrate (157 mg, 0.66 mmol) and (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (1.07 g, 3.31 mmol) in methanol (30 mL) was cooled to 0° C. and then treated with sodium borohydride (380 mg, 10 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The black solid was filtered using filter paper and washed with methanol. The combined solvents were concentrated in vacuo, and the residue was diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.04 g, 97%) as an amorphous white solid: EI-HRMS m/e calcd for C17H24O4S (M+) 324.1395, found 324.1395.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].Cl[C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]#[C:27][CH3:28])[N:21]=[CH:20][N:19]=1.[Cl-].[NH4+]>O1CCCC1>[C:15]([CH:14]([C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]#[C:27][CH3:28])[N:21]=[CH:20][N:19]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])#[N:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: N#CCc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C#N)c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
In 40 ml of tetrahydrofuran was suspended 4.61 g of potassium t-butoxide, to which 4.44 g of (2-fluorophenyl)acetonitrile was added under ice cooling. Then, a solution of 5.00 g of 4-chloro-6-(2-butynyloxy)pyrimidine in 20 ml of tetrahydrofuran was added at 0° C., followed by stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 6.40 g of 4-(α-cyano-2-fluorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (145)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (361 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionic acid tert.-butyl ester (Example K12) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (367 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:6](Cl)[N:5]=[C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7]1[C:6]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[N:5][C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][C:2]=1[Cl:1]
Reactant: Clc1nc(C2CCOCC2)nc(Cl)c1-c1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCOCC3)nc(Cl)c2-c2nc3ccccc3s2)C1
Yield: 78.6 %

Procedure:
Following the same procedure as in step 4 of Example 21 using 2-[4,6-dichloro-2-(oxan-4-yl)pyrimidin-5-yl]-1,3-benzothiazole (90 mg, 0.25 mmol, 1.00 equiv), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (49 mg, 0.24 mmol, 1.00 equiv), and N,N-Diisopropylethylamine (63 mg, 0.49 mmol, 1.98 equiv) in ethanol (2 mL). The reaction mixture was concentrated under reducing pressure to afford 100 mg of the title compound as a yellow solid, which was used directly for next step without further purification. 1H-NMR (CDCl3, 400 MHz,): δ ppm 1.29 (s, 9H), 1.73 (s, 1H), 1.90-2.08 (m, 8H), 2.98 (m, 8H), 3.00 (m, 1H), 3.30-4.48 (m, 10H), 7.33-7.50 (m, 2H), 7.46-8.06 (m, 4H), 11.09 (d, J=6.8, 1H).
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:3])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)N(Cc3ccccc3)C(C)C)=C21
Reaction time: 8 h

Procedure:
To the solution of 5.0 g of the slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride in 66 ml of anhydrous ethanol are added 3.64 g of anhydrous potassium carbonate and 3.14 ml of benzyl bromide. The mixture is refluxed for 3 hours while stirring and half of the original quantities of potassium carbonate and benzyl bromide are added. Refluxing is continued overnight and a second addition of the same reagents and refluxing for an additional day leads to complete benzylation. The mixture is evaporated, the residue diluted with water, extracted with chloroform and the extract dried and evaporated. The crude product is crystallized from petroleum ether and recrystallized from ethanol to give the 1-[2-(N-isopropyl-N-benzylamino)-propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, melting at 205°-207°.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH3:13]I>O1CCCC1>[CH3:13][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)oc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
NaH (280 mg, 7.00 mmol) was added to a chilled (0° C.) solution of benzo[d]oxazol-2(3H)-one (650 mg, 4.81 mmol) in tetrahydrofuran (20 mL). After 0.5 hours, methyl iodide (1.03 g, 7.25 mmol) was added dropwise with stirring, maintaining a temperature of 0° C. The resulting solution was then stirred for 6 hours at room temperature. The reaction mixture was then quenched by the addition of ethanol (10 mL), and the mixture was concentrated. Water (50 mL) was then added and the resulting solution was extracted with dichloromethane (3×20 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated to afford 0.62 g (82%) of 3-methylbenzo[d]oxazol-2(3H)-one as a light red solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13])([O-])=O>[Fe]>[F:13][C:12]([F:14])([F:15])[C:5]1[CH:6]=[C:7]([CH2:10][CH3:11])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Fe]
Product: CCc1ccc(N)c(C(F)(F)F)c1
Yield: 98.8 %

Procedure:
61 g of 2-nitro-5-ethylbenzotrifluoride were reduced analogously to Example 4 by means of iron. 52 g of 2-trifluoromethyl-4-ethylaniline (boiling point: 96°-8° C./20 mbar, nD20 : 1.4788) are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31][CH2:30]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Solvent: CC#N
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CN3CCN(CCO)CC3)cc2CO1
Yield: 244.4 %

Procedure:
Prepared from 2-chloro-N-[2-(2-methoxy-benzylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 26 step A) (50 mg, 0.129 mmol, HPLC 0.889 min 81%) and 1-(2-hydroxyethyl)piperazine (1 ml, 8 mmol) in acetonitrile (3 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (143 mg, 79%, HPLC 0.379 min), MS (ISP) m/e=454.3 [(M+H)+].
Reaction SMILES: [CH:1]1([C:7]2([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16][CH:17]1[CH2:22][NH:21][C:20](=[N:23][N+:24]([O-:26])=[O:25])[NH:19][CH2:18]1.CN(C=O)C>C(#N)C>[CH:1]1([C:7]2([C:13]([O:16][CH:17]3[CH2:18][NH:19][C:20](=[N:23][N+:24]([O-:26])=[O:25])[NH:21][CH2:22]3)=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1(C2CCCCC2)CCCCC1
Reactant: O=[N+]([O-])N=C1NCC(O)CN1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(OC1CNC(=N[N+](=O)[O-])NC1)C1(C2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-cyclohexylcyclohexane-1-carbonyl chloride (2.1 g) in acetonitrile (30 ml), 5-hydroxy-2-nitroiminohexahydropirimidine (1.28 g) was added portionwise. The mixture was stirred at room temperature overnight, then DMF (10 ml) was added and the mixture was heated to 50° C. for 24 hours. The reaction was quenched with water. The precipitate was collected, dried and triturated with diethyl ether to afford 0.93 g of 2-nitroiminohexahydropyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:17]([O:24][C:25]1[C:30]([CH2:31]Cl)=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1>O1CCOCC1>[CH2:17]([O:24][C:25]1[C:30]([CH2:31][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[N:4][CH:5]=3)[C:10]2=[O:12])=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)Oc1ncc2c(c1Cl)C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3cnc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 100 °C
Yield: 18.9 %

Procedure:
To a mixture of 8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112e, 60.0 mg, 0.250 mmol) and 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 78 mg, 0.3 mmol) in 1,4-dioxane (3 mL) was added KHMDS in THF (1.0 M, 1.24 mL, 1.24 mmol). The reaction mixture was heated at 100° C. for 1 hour, then cooled to room temperature. The reaction mixture was concentrated, H2O (10 mL) was added, and the aqueous layer extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under vacuum and the residue purified by preparative HPLC to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112f, 22 mg, 19% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][N+:5]=1[O-:13].[CH:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][O:18][C:8]2[CH:7]=[CH:6][N+:5]([O-:13])=[C:4]([CH3:3])[CH:9]=2)[CH2:16][CH2:15]1
Reactant: OCC1CC1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OCC2CC2)cc[n+]1[O-]
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To sodium hydride (55% pure) (4.4 g, 0.1 mol) (washed with petroleum ether), cyclopropyl-methanol (50 ml) was added. Then a solution of 2-methyl-4-nitropyridine-N-oxide (6.5 g, 0.042 mol) in cyclopropylmethanol (30 ml) was added during about 1 h. The dark brown mixture was heated to 90° C. and stirred at 90° C. for about 1 h. Thereafter the cyclopropylmethanol was distilled off under reduced pressure and methylene chloride (100 ml) was added to the residue. The mixture was stirred for about 30 minutes, then filtered and concentrated which gave 9.5 g of crude material.