Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)=[N:8][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[NH:4][N:3]=1.[NH2:34][NH2:35]>CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:23][CH:22]=3)=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:34][NH2:35])=[O:16])=[CH:19][CH:20]=3)=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2cc3[nH]nc(N)c3c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Solvent: CN(C)C=O
Product: NNC(=O)c1ccc(-c2cc3[nH]nc(N)c3c(-c3ccc(Oc4ccccc4)cc3)n2)cc1

Procedure:
A solution of methyl 4-(3-amino-4-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)benzoate (28 mg, 0.064 mmol, from Example 192) and hydrazine (20 μL 0.637 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at 100° C. for 3 h. LC-MS showed that only small amount of the desired product was formed. A 35% aqueous solution of hydrazine (0.5 mL) was added. After additional 1 h at 100° C., the mixture was cooled to give a suspension. Water was added and the mixture filtered. The solid was washed with water, dried under vacuum to give Example 194 (19 mg, 67% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2H, δ, J=8.53 Hz), 7.91 (2H, δ, J=8.53 Hz), 7.81-7.85 (2H, m), 7.71 (1H, s), 7.42 (2H, t, J=8.03 Hz), 7.16-7.22 (3H, m), 7.13 (2H, dd, J=8.66, 1.13 Hz); MS (ES+) m/z: 437 (M+H); LC retention time: 2.801 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:28]=[C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH3:49])=[C:35]([NH:37][C:38]([C:40]2[N:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]3=[N:42][CH:41]=2)=[O:39])[CH:36]=1)[NH2:30]>CN1C(=O)CCC1>[N:42]1[CH:41]=[C:40]([C:38]([NH:37][C:35]2[CH:36]=[C:31]([C:29]3[N:28]=[C:12]([CH:10]4[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]4)[O:14][N:30]=3)[CH:32]=[CH:33][C:34]=2[CH3:49])=[O:39])[N:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=12
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of Boc-azetidine-3-carboxylic acid (162 mg, 0.8 mmol) in anhydrous NMP (4 mL) was added CDI (131 mg, 0.8 mmol). The reaction was stirred for 2 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (250 mg, 0.8 mmol) was added and the reaction was stirred for 15 minutes, then heated via microwave at 120° C. for 15 minutes. The crude was purified by reverse phase HPLC to afford tert-butyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F13) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s 1H), 9.51 (d, J=6.8 Hz, 1H), 8.70 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.86 (dt, J=12, 2.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.31 (td, J=6.8, 0.8 Hz, 1H), 4.06-4.38 (m, 5H) 2.37 (s, 3H), 1.40 (s, 9H). MS m/z 476.2 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[NH:16][C:13]2[CH:14]=[CH:15][C:10]([N:7]3[C:6]4[CH:31]=[CH:32][C:3]([NH:2][C:33](=[O:35])[CH3:34])=[CH:4][C:5]=4[N:9]=[CH:8]3)=[CH:11][CH:12]=2)=[CH:21][C:22]=1[C:27]([F:29])([F:30])[F:28]
Reactant: Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-[5-aminobenzimidazol-1-yl]phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and acetic anhydride by the same method as in Example 41.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and ethyl 4-iodobenzoate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(OCC)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2cc(I)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)ccc2c1O
Temperature: 180 °C

Procedure:
3-Iodoaniline (8.50 mL) and diethyl ethoxymethylenemalonate (14.30 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 70 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid filtered, washed with hexanes, and dried. The solid is triturated in ethyl acetate to give 12.82 g of ethyl 4-hydroxy-7-iodoquinoline-3-carboxylate. A mixture of this ester (0.35 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to 70° C. and poured into 50 mL diethyl ether. A tan solid which crystallizes slowly out of diethyl ether is obtained. The solid is recrystallized from ethyl acetate/hexanes to give the desired product (0.22 g).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(C)(N)CO
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 29 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (537 mg, 1.5 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (155 mg, 29%) which was obtained as a white solid after purification by chromatography (silica, 0 to 60% ethyl acetate in heptane). MS: m/e=362.4 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH:14]([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][CH:14]([CH3:17])[CH3:13])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: C#CC(C)C
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#CC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (Aldrich, 10 g, 35.8 mmol) in Et3N (60 ml) and DMF (6 ml) was added CuI (34 mg, 0.18 mmol), Pd(PPh3)2Cl2 (126 mg, 0.18 mmol), and 3-methyl-1-butyne (5.0 ml, 73.5 mmol). The mixture was stirred at room temperature for 16 h and was concentrated. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→15% EtOAc-hexanes) to yield the title compound as a brown oil.
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[N:11]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C@H:24](O)[CH2:23][C@H:12]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl.O>[CH2:16]([O:15][C:13](=[O:14])[C@H:12]1[CH2:23][C@H:24]([F:8])[CH2:26][N:11]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: FS(F)(F)N1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Morpholinosulfur trifluoride (morph-DAST; 3.5 mL, 29 mmol) was added by syringe to a solution of 1 (6.5 g, 20 mmol) in dry CH2Cl2 (200 mL) under Ar(g) at −78° C. The solution w allowed to warm to room temperature and stirred overnight. Following a quench with methanol, the reaction mixture was washed with 2×100 mL saturated NaHCO3(aq). An emulsion resulted, so the mixture was diluted with H2O and CH2Cl2 and filtered through Celite. The biphasic filtrate was separated, and the organic layer was washed with water, dried over MgSO4(s), and concentrated by rotary evaporation under reduced pressure. The resulting oil was purified by flash chromatography (1.5% v/v MeOH in CH2Cl2), which afforded 11 (3.1 g, 9.6 mmol, 48%) as a yellow oil. An additional 2.32 g of 11 that were contaminated with a minor impurity, as indicated by TLC, were also obtained from the column.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:6]([CH:17]=1)[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.[ClH:23].O1CCOCC1>CCOC(C)=O>[ClH:23].[CH2:21]([S:18]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:17][C:6]=1[CH2:7][NH:8][CH3:9])(=[O:19])=[O:20])[CH3:22]
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(N)cc1CNC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3B (2 g, 6.09 mmol) in EtOAc (30 mL) was added 4.0 N HCl in dioxane (30.4 mL, 122 mmol) and the mixture was stirred at r.t. for 2 h. Solvent was removed under reduced pressure to give 3C (1.8 g, 6.27 mmol, 99% yield) as a off white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.79 (d, J=8.79 Hz, 1H) 7.03 (d, J=2.20 Hz, 1H) 6.96-7.02 (m, 1H) 4.33 (s, 2H) 3.24 (q, J=7.47 Hz, 2H) 2.75 (s, 3H) 1.24 (t, J=7.47 Hz, 3H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)OCC)C.[CH2:16]([N:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:23]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: O=Cc1ccn(Cc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 311 mg, 7.8 mmol) in DMF (15 ml) was added dropwise at an ice bath temperature a solution of diethyl(methoxycarbonylmethyl)phosphonate (1.64 g, 7.8 mmol) in DMF (3 ml). The mixture was stirred for 30 minutes at room temperature and cooled again. To the mixture was added dropwise a solution of 1-benzyl-3-formylpyrrole (1.2 g, 6.5 mmol) in DMF (2 ml). The reaction mixture was stirred for 12 hours at room temperature and poured into ice-water, and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained white crystal was washed with i-Pr2O to give 1-benzyl-3-(2-methoxycarbonylvinyl)pyrrole (1.3 g). Yield: 83%.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: Oc1ccccc1
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: c1ccncc1
Product: C[n+]1ncc(N)cc1Oc1ccccc1

Procedure:
12.2 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 150 parts of acetonitrile is stirred with 5 parts of phenol and 4 parts of pyridine for 4 hours at 80°C. The reaction mixture is filtered and the filtrate is concentrated at subatmospheric pressure. About 200 parts of water is added. 5.5 parts (36.6% of theory) of 1-methyl-4-amino-6-phenoxypyridazinium perchlorate is obtained; C11H12O5N3Cl, melting point 182° to 184°C after having been recrystallized from water.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].I[CH2:34][CH2:35][CH:36](Br)[CH2:37][CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:36]([CH2:37][CH3:38])[CH2:35][CH3:34])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCC(Br)CCI
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(CC)CC)C2)c1
Temperature: 78 °C
Yield: 75 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (42 mg, 0.093 mmol) in CH3CN (0.5 ml) was added 1-iodo-3-Bromopentane (21.0 mg, 0. 14 mmol) and cesium carbonate (61.0 mg, 0.186 mmol). The reaction was heated to 78° C. overnight. The subsequent addition of the reactants as described above and allowing the reaction to continue over a second night, resulted in ˜75% product: starting material. The reaction was cooled to room temperature, concentrated in vacuo, diluted with EtOAc, washed with NaHCO3, and brine. The solution was filtered, and concentrated, then purified via silica gel chromatography to give the product as a clear oil. (32.7 mg, 68% ) Calculated for C31H42F3NO2 (M+H) 517.67, Found 518.4.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)[Cl:15]>>[CH2:1]([Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: ClP(Cl)Cl
Product: CCCCCCCCCCCCCl
Temperature: 165 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
Into a reactor system in accordance with FIG. 1 there were pumped jointly per hour 1.65 kg lauryl alcohol (purity: 97%) and 0.41 kg phosphorus trichloride. The cooling was performed in reaction zone 1 in such a way that the outlet temperature was about 110° C. The residence time in reaction zone 1 was 5 minutes. Following preheating to 150° C for 2.5 minutes, the reaction mixture reached reaction zone 2 in which the reaction temperature was maintained with superheated steam at 165° C. The residence time in reaction zone 2 was 26 minutes. By means of a pressure maintenance valve, the entire reactor system was under a pressure of 30 atm. The product obtained in this manner separated out immediately into two phases. One obtained per hour 1.8 kg of the organic phase corresponding to a yield of 97.5% of lauryl chloride with respect to lauryl alcohol. The purity amounted to 95 weight-percent of lauryl chloride. The product contained 0.14 weight-percent of dilauryl ether. Space-time yield: 1.4 kg/hour, liter.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:15][NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[CH2:1]([O:15][NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1NO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1NOCc1ccccc1
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirring suspension of benzyl bromide (1.038 g, 6.07 mmol) and cesium carbonate (2.70 g, 8.28 mmol) in DMF (4 mL) was added ethyl 2-(hydroxyamino)benzoate (1.0 g, 5.52 mmol) dissolved in 2 mL DMF at RT and stirred for 1 h. Reaction mixture was diluted with water and extracted with EtOAC. The organic layer was separated and distilled out to get crude product which was column purified using 0-3% EtOAC in hexane to get the titled compound in 72% yield.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([CH2:13][CH:14]=O)[C:8]([O:10]CC)=O)=[C:4]([Cl:18])[CH:3]=1.Cl.[NH:20]1[C:28]2[CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24][C:23]=2[CH:22]=[N:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]2[CH2:13][CH2:14][N:29]([CH:26]3[CH2:27][C:28]4[C:23](=[CH:22][NH:21][N:20]=4)[CH2:24][CH2:25]3)[C:8]2=[O:10])=[C:4]([Cl:18])[CH:3]=1
Reactant: CCOC(=O)C(CC=O)Cc1ccc(Br)cc1Cl
Reactant: NC1CCc2cn[nH]c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCc2c[nH]nc2C1
Yield: 37.4 %

Procedure:
Combine ethyl 2-(4-bromo-2-chlorobenzyl)-4-oxobutanoate (0.92 g, 2.8 mmol), 4,5,6,7-tetrahydro-1H-indazol-6-amine hydrochloride (preparation 80) (490 mg, 2.8 mmol) and sodium triacetoxyborohydride (886 mg, 4.2 mmol) in dichloroethane (50 mL) and stir for 48 hours at room temperature. Add water and extract with CH2Cl2. Dry the organic layer over magnesium sulfate, filter and concentrate. Purify the residue by silica gel chromatography affords the title compound (428 mg, 68%): MS (m/z): 410 (M+2).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[C:24]([CH3:27])[CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1COCC1.[NH:37]1[CH2:40][CH2:39][CH2:38]1>>[N:37]1([C:22]2[N:21]=[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:29])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])[C:25]([Br:26])=[C:24]([CH3:27])[CH:23]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cc1cc(Cl)nc(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1Br
Reactant: C1CNC1
Solvent: C1CCOC1
Product: Cc1cc(N2CCC2)nc(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1Br
Temperature: 150 °C

Procedure:
In a microwave tube, (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloro-4-methylpyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.940 mmol) was dissolved in a 2M solution of azetidine in THF (8 mL, 16.0 mmol). The tube was sealed and the reaction was heated to 150° C. for 2 hr in the microwave. The reaction was then cooled and concentrated. The residue was purified via flash chromatography on silica gel (0 to 75% ethyl acetate/hexanes) to afford (4S,5R)-3-[(6-azetidin-1-yl-3-bromo-4-methylpyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=551.9 and 553.9 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.77 (s, 2H), 6.09 (s, 1H), 5.77 (d, J=8.7 Hz, 1H), 4.87 (d, J=17.2 Hz, 1H), 4.37 (m, 1H), 4.21 (d, J=16.9 Hz, 1H), 3.99 (m, 4H), 2.38 (m, 2H), 2.30 (s, 3H), 0.77 (d, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[CH:30]=[O:31]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:34]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][C:27]=3[Br:26])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N-(4-chlorophenethyl)-4-hydroxybenzamide (1.5 g, 5.4 mmol) was diluted with DMSO (15 mL) followed by the addition of K2CO3 (0.89 g, 6.4 mmol) and 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol). The reaction was stirred at 85° C. overnight and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and then concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (1:1) and then 100% ethyl acetate to yield N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenoxy)benzamide (1.6 g, 71% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].C(OC(C1C(=O)C2C(=CC=CN=2)N(CC2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17]([N:7]([CH2:9][C:38]3([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:39][CH2:40][CH2:41][CH2:42]3)[CH:6]=1)=[N:16][CH:15]=[CH:14][N:13]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1nccnc1Cl
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Product: CCOC(=O)c1cn(CC2(c3ccccc3)CCCC2)c2nccnc2c1=O
Yield: 30 %

Procedure:
8-Oxo-5-(1-phenyl-cyclopentylmethyl)-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester (16) (600 mg, 30%) was synthesized as a brown sticky liquid from 1.5 g of 2-(3-chloro-pyrazine-2-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (13) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][O:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:1][C:2]1[C:12]2[CH2:11][O:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][C:18]3[CH:19]=[C:20]([NH:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 90, the title compound is prepared from 3-(7-chloro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-phenylamine and methanesulfonyl chloride. Elute on silica gel with 15% ethyl acetate:toluene gave 530 mg product (86%). 1H NMR (400 MHz, CDCl3) δ 7.463-7.443 (d, 1H), 7.358-7.337 (d, 1H), 7.230-7.155 (m, 2H), 7.116-7.077 (t, 1H), 7.016-6.840 (m, 7H), 6.264 (s, 1H), 5.563 (s, 2H), 2.88 (s, 3H) MS m/z: 410.1 (M−−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1ccc(COC(=O)c2c(Cl)ncnc2Cl)cc1
Solvent: C1COCCO1
Product: COc1ccc(COC(=O)c2c(N)ncnc2Cl)cc1
Temperature: 0 °C
Yield: 119.4 %

Procedure:
4-Methoxybenzyl 4,6-dichloropyrimidine-5-carboxylate (732 m g, 1.97 mmol) was dissolved in dioxane (14 ml) and cooled in an ice bath. Ammonia (1.41 ml, 7N in MeOH, 9.87 mmol) was dropwise added and the mixture was stirred at 0° C. and then stirred at room temperature overnight. The solvent was removed to give 691 mg (94% yield) of the title compound, that was used in the next step without further purification. Purity 79%