Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([OH:36])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([OH:36])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(C(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: ClC(Cl)C(O)=O.N[C:8]1[N:9]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([CH:35]3[CH2:37][CH2:36]3)=[CH:30][C:29]=2[Cl:38])[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1.N([O-])=O.[Na+].ClCCl.[Br:46]CBr>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:46][C:8]1[N:9]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([CH:35]3[CH2:37][CH2:36]3)=[CH:30][C:29]=2[Cl:38])[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1
Reactant: BrCBr
Reactant: Cc1cc(C2CC2)cc(Cl)c1-n1c(N)nnc1SCC(=O)Nc1ccc(C(=O)O)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Solvent: ClCCl
Product: Cc1cc(C2CC2)cc(Cl)c1-n1c(Br)nnc1SCC(=O)Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
Dichloroacetic acid (0.065 mL, 0.78 mmol) was added to, a mixture of compound 6 (192 mg, 0.39 mmol), benzyltriethyl ammonium bromide (318 mg, 1.17 mmol) and sodium nitrite (538 mg, 7.8 mmol) in dibromomethane (10 mL). The mixture was stirred at room temperature for 18 hours in the dark. The reaction mixture was then concentrated and the resulting residue was purified by prep. TLC (95% dichloromethane/5% methanol) to afford 88 mg, 42% yield of 4-(2-(5-bromo-4-(2-chloro-4-cyclopropyl-6-methylphenyl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (7).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[N:21]([C@@H:24]1[CH2:28][NH:27][CH2:26][C@H:25]1[OH:29])=[N+:22]=[N-:23]>>[N:21]([C@@H:24]1[CH2:28][N:27]([C@H:7]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:26][C@H:25]1[OH:29])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=N[C@@H]1CNC[C@H]1O
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Product: [N-]=[N+]=N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@H]1O

Procedure:
Prepared as described in Example 9B using (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (5.06 g, 14.7 mmol) and (3R,4R)-4-azidopyrrolidin-3-ol (2.08 g, 16.2 mmol) in place of (S)-tert-butyl pyrrolidin-3-ylcarbamate in Step D (2.44 g, 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccncn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2ccncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 18) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:3]=1.[OH-].[NH4+:24]>>[NH2:24][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Br)c3c(Cl)ncnc32)C1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CC(n2cc(Br)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To 1,1-dimethylethyl 3-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (690 mg, 1.780 mmol) was added ammonium hydroxide (69.3 μl, 1.780 mmol) in a 20 mL microwave vial. The vial was capped heated at 100° C. for a total of 2 hr in the microwave reactor. The reaction was checked every 0.5 hr. Only 15% desired product was observed. The reaction was filtered. The solid was added NH4OH (4 mL) into a 20 ml microwave vial and the vial was heated in an oil bath at 90° C. for 24 hr. The reaction observed 80% product. Additional 1 ml of NH4OH was added and heating continued overnight. The reaction was filtered and washed to give 1,1-dimethylethyl 3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (538 mg) in 78% purity. LC-MS (ES) m/z=368.2, 370.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[C:28]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]([O:36][CH2:37][CH3:38])=[O:35])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CO)cc3C)cc12
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)C(=O)OCC
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol (from Example 65/Step 1) (0.2 M) and diethyl malonate (2 eq) in dry toluene was added tributylphosphine (2 eq) and N1,N1,N2,N2-tetramethyldiazene-1,2-dicarboxamide (2 eq). The reaction mixture was stirred at 120° C. overnight. Upon completion of the reaction, the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford diethyl 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzyl)malonate as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1.[C-]#N.[K+].[CH3:24][N:25](C)C=O>O>[C:24]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)#[N:25]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(OCCc2ccc(CCl)cn2)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 5-chloromethyl-2-[2-(4-nitrophenoxy)-ethyl]pyridine (9.5 g), potassium cyanide (3.2 g) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 5-cyanomethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.0 g, yield: 98%). This compound was recrystallized from ethyl acetate-hexane to obtain colorless prisms, m.p. 94°-95° C.
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>ClCCl.O>[CH:14]1([NH:20][C:11]([CH2:12][C:1]2([CH2:7][C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)CC1(CC(=O)NC2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.9 %

Procedure:
A mixture of 1,1-cyclohexanediacetic anhydride (0.911 g, 5.0 mmol) and cyclohexylamine (0.63 mL, 5.5 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with H2O (5 mL) and the aqueous layer was acidified to pH-5 using 6 N HCl. The organic layer was collected. The aqueous layer was extracted with additional dichloromethane (5 mL). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated to dryness to give crude title compound (1.63 g, 95% purity). (m/z): [M+H]+ calcd for C16H27NO3, 282.21; found 282.5.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.[CH2:28]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:28]([C:33]1[CH:34]=[CH:35][C:36]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[O:26])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[CH:37][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: CCCCCc1ccc(B(O)O)cc1
Product: CCCCCc1ccc(-c2ccc(OC(CCC)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
This compound is made in a substantially similar manner as Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl ester and 4-pentylphenylboronic acid as starting materials in step D. MS (ES): 488.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16](=O)[CH3:17])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.C([BH3-])#[N:36].[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.O.C(O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:16]([CH3:17])[NH:36][C:10]1=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(CC(C(C)=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: CC1NC(=O)C(NC(=O)OC(C)(C)C)CC1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoate (21.6 g, 58.4 mmol) in methanol (200 mL) were added ammonium acetate (45.0 g, 584 mmol), acetic acid (50.2 mL, 876 mmol), and sodium cyanoborohydride (5.51 g, 87.7 mmol). The mixture was heated at 60° C. for a total of 4 h. The mixture was then allowed to cool to ambient temperature and sodium bicarbonate and water were added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Ethanol (240 mL) and potassium carbonate (40.4 g, 292 mmol) were added. The mixture was stirred 1.5 h at 60° C. to effect epimerization to the desired epimer. Water was added followed by extraction with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 0.1% ammonium hydroxide) gave the title compound as a mixture of isomers. MS: m/z=361.2 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@H]2[C@@H](O)C[N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C@@H:19]([OH:27])[CH2:20][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl (3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.39-7.25, 5.18, 4.99, 4.89, 4.71, 4.55, 4.04, 3.75-3.58, 3.36, 2.69, 2.49, 1.30, 1.15; HRMS (FAB) calcd for C26H28Cl2N4O3+H 515.1616, found 515.1641.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COC(=O)c1ccc(SC)cc1O
Product: COC(=O)c1ccc(SC)cc1OCCCNC(=O)OC(C)(C)C

Procedure:
Methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoate was prepared (7.0 g, 82%) as described in Example 1-D from methyl 2-hydroxy-4-(methylthio)benzoate and 3-tert-butoxycarbonylaminopropanol.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:12]3[C:13]([OH:16])=[N:14][O:15][C:11]=3[C:10]=2[F:21])[CH2:3]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:12]3[C:13]([O:16][CH3:22])=[N:14][O:15][C:11]=3[C:10]=2[F:21])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(O)noc3c2F)C[C@H](C)O1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-hydroxy-1,2-benzisoxazole-5-carbaldehyde (Intermediate 556, 0.15 g, 0.5 mmol) in acetonitrile was added K2CO3 (0.08 g, 0.6 mmol) followed by MeI (0.07 mL, 0.5 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, washed with water and extracted with EtOAc (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide the title product, along with a by-product, 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-2-methyl-3-oxo-2,3-dihydro-1,2-benzoxazole-5-carbaldehyde. The mixture was used in the next step with out further purification.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([C:12]([NH:14][C:15]2[C:16](Cl)=[N:17][CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1>>[CH:1]1([N:4]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[NH:14][C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[N:17][C:16]2=3)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 l of diglyme (diethylene glycol-dimethylether) to 135°-145° C. for about 30 minutes in a 1200 l VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material (4) is reacted. To this mixture, over about 30 minutes at 135°-145° C., a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material (4) is reacted. The mixture is then kept at 135°-145 ° C. for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 144 l of diglyme. The filtrates are combined and 400 l of solvent is distilled off. The residue is then diluted with a further 287 l of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 144 l of diglyme and the mixture is stirred at a temperature of 130° to 140° C. for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 l of water. After the reaction mixture has been cooled to a temperature of about 25° C., 575 l of cyclohexane and 147 l of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 l of methyl-tert.-butylether, followed by 862 l of water and finally with 575 l of ethanol. In this way, after drying, 225 kg (83.0% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b :2',3'-e][1,4 ]diazepin-6-one (nevirapine) is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27](=O)[CH2:28]Br>O>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3cccc(F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 57 %

Procedure:
4-[4-(3-Fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (150 mg, 57%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-fluorophenacyl bromide (available from Aldrich Chemical Company, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.25-8.28 (m, 2H), 8.10-8.17 (m, 3H), 7.63-7.82 (m, 2H), 7.30-7.48 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[OH:13].C[O-].[Na+]>C(O)C>[Br:1][CH2:2][CH2:3][O:13][C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=1[CH3:5]
Reactant: BrCCBr
Reactant: Cc1ccc(C)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C)c(OCCBr)c1
Temperature: 65 °C

Procedure:
A solution of 75.2 g (0.4 mol) 1,2-dibromoethane in 80 mL of anhydrous ethanol was stirred and heated to 65° C. under a nitrogen atmosphere, and then a solution of 24.4 g (0.2 mol) of 2,5-dimethylphenol and 10.8 g (0.2 mol) of NaOMe in anhydrous ethanol (100 mL) was added into the above solution dropwise. After finish adding, refluxed for 5 hours. The mixture was cooled to room temperature, washed and extract d with ethyl ether, 2M NaOH solution and deionized water. The organic phase was collected, dried with CaCl2 and then filtered. After evaporating the solvent from the filtrate, 1-(2′-bromoethanoxy) 2,5-dimethylbenzene was purified by vacuum distillation. 1H-NHR (CDCl3, ppm): δ 7.00 (d, 1H), δ 6.4 (d, 1H), δ 6.6 (s, 1H), δ 4.24 (t, 2H), δ 3.62 (t, 2H), δ 2.3 (s, 3H), δ 2.2 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]([F:25])([F:24])C(OCC)=O.O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:18]([F:25])[F:24])=[C:4]([Cl:10])[CH:3]=1
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: FC(F)Oc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a stirred solution of 4-bromo-2,6-dichlorophenol (2.3 g) in acetonitrile (25 mL) was added potassium carbonate (1.3 g) and ethyl bromodifluoroacetate (3.8 g). The mixture was heated to reflux for 4 hours and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4) to afford the title compound as yellow oil (2.4 g).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]3)[O:3]1.CC([O-])=O.[NH4+].CC(C)=O>O>[CH2:21]([O:20][C:18]([CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([B:4]([OH:5])[OH:3])[CH:10]=2)[CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1Cc2ccc(B(O)O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixture of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-2-carboxylate (16 g, 50% purity, 25.3 mmol), NaIO4 (24 g, 0.112 mol), CH3COONH4 (5.2 g, 0.068 mol), acetone (100 mL), and water (10 mL) was stirred at room temperature overnight. The acetone was evaporated, and the aqueous residue was extracted with EtOAc (3×100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound as white solid (3.5 g). 1HNMR (400 MHz, DMSO-d6): δ 7.91 (s, 2H), 7.62 (s, 1H), 7.57 (d, 1H), 7.17 (d, 1H), 4.10 (q, 2H), 3.36-3.32 (m, 1H), 3.09-3.07 (m, 4H), 1.20 (t, 3H).
Reaction SMILES: [OH:1][P:2]([O-:5])([O-:4])=[O:3].[Ca+2:6].C(=O)([O-])[O-].[Ca+2]>[Pt].O>[O-:3][P:2]([O-:5])([O-:4])=[O:1].[O-:3][P:2]([O-:5])([O-:4])=[O:1].[Ca+2:6].[Ca+2:6].[Ca+2:6]
Reactant: O=P([O-])([O-])O
Agent: [Pt]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 1400 °C
Reaction time: 72 h

Procedure:
For a mixture of 500 g (dry weight), 360 g dicalcium phosphate anhydrous powder, 144 g calcium carbonate powder and 220 ml deionized water were mixed for 7 minutes at 500 rpm using a laboratory stirrer. The slurry from the mixing process was immediately transferred into a high temperature stable platinum cup. The filled platinum cup was placed in a cold furnace. The furnace was heated to 1400° C. by using a heating rate of 60° C. per hour. The heating process was stopped after 72 hours by switching off the furnace. The sample was cooled down to room temperature within the furnace. The bulk sintered material (phase pure α-Ca3(PO4)2) was removed from the furnace and the platinum cup. The bulk product from the sintering process had a weight of 420 g (weight loss 16.7%).