Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][CH2:21][O:22]C3CCCCO3)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(OCCOC2CCCCO2)c2ccc(F)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2)c(OCCO)c2ccc(F)cc12
Temperature: 55 °C
Yield: 95 %

Procedure:
To a solution of 590 mg (1.54 mmol) of 7-fluoro-3-phenyl-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]isoquinolin-1(2H)-one in methanol (12 mL), 88 mg of p-toluenesulphonic acid (0.46 mmol) were added and the resulting mixture was heated at 55° C. for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed twice with aqueous sodium hydrogencarbonate saturated solution. The combined organic layer were dried over sodium sulphate and concentrated under reduced pressure to afford 438 mg of the title compound (95%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]2[CH2:7][S:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:4]2[NH:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:82])[NH:66][C:67]3[CH:72]=[CH:71][C:70]([NH2:73])=[C:69]([O:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)[CH:68]=3)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1>CC(N(C)C)=O>[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:82])[NH:66][C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]4[CH:4]5[CH:5]([NH:6][C:2](=[O:1])[NH:3]5)[CH2:7][S:8]4)=[C:69]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:68]=3)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Reactant: O=C(O)CCCCC1SCC2NC(=O)NC21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid (388) (0.293 g, 1.2 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.455 g, 1.2 mmol) were combined and dissolved in DMA (24 mL). iPr2EtN (0.313 mL, 1.8 mmol) was added and the mixture was shaken for 30 minutes at room temperature. The (4-amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (65) (0.25 g, 0.573 mmol) was added and the mixture was shaken in a 40 mL I-Chem vial for 16 h. LC-MS indicated complete coupling at this point. The mixture was poured into ice-water and a very pale/purple powder precipitated. Collection by filtration under reduced pressure followed by drying under high vacuum for 16 h gave the desired product (389) as a white/purple solid (0.28 g, 0.422 mmol, 73.7% yield). LC-MS (ESI): (exact mass: 662.26) m/e 663.2 [M+1]+ (100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:18]=2)[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)=[O:4].Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:18]=2)[CH2:6][CH2:7][C:8](=[O:9])[CH2:13][CH2:14]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid methyl ester (4.7 g, 9.7 mmol; intermediate in the synthesis of example 54) was dissolved in dioxane (70 ml), 2 N aqueous hydrochloric acid (10 ml) was added and the mixture was stirred at room temperature overnight. The material was partitioned between EA and saturated aqueous sodium chloride solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH:11]([C:13]2[O:17][N:16]=[C:15]([CH:18]3[CH2:23][CH:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH2:21][N:20]([C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:19]3)[N:14]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH:9]1[CH2:10][CH:11]([C:13]2[O:17][N:16]=[C:15]([CH:18]3[CH2:23][CH:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH2:21][N:20]([C:34]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:35])[CH2:19]3)[N:14]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)no2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2noc(C3CNC3)n2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.30 ml (1.16 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 67 mg (0.117 mmol) of the compound from Example 92A in 0.6 ml of dioxane. The reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated using a rotary evaporator and once more taken up in 0.6 ml of dioxane, and 0.3 ml (1.16 mmol) of a 4N solution of hydrogen chloride in dioxane was added. The reaction mixture was stirred at room temperature overnight and then concentrated to dryness under reduced pressure and dried until the weight remained constant. Yield: 58 mg (100% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1.[F:11][C:12]1([F:58])[CH2:17][CH2:16][CH:15]([C:18]2[C:27]3[CH:26]([O:28]CC4C=CC(OC)=CC=4)[CH2:25][C:24]([CH3:39])([CH3:38])[CH2:23][C:22]=3[N:21]=[C:20]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:19]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:14][CH2:13]1>>[F:58][C:12]1([F:11])[CH2:17][CH2:16][CH:15]([C:18]2[C:27]3[CH:26]([OH:28])[CH2:25][C:24]([CH3:38])([CH3:39])[CH2:23][C:22]=3[N:21]=[C:20]([CH:40]3[CH2:45][CH2:44][N:43]([C:2]4[N:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=4)[CH2:42][CH2:41]3)[C:19]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:49][CH:48]=2)[CH2:14][CH2:13]1
Reactant: CC(C)c1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CC(C)c1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-(propan-2-yl) pyrimidine instead of 5-bromo-2-chloropyrimidine, and from 96 mg (0.14 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 47 mg of the title compound was obtained as a white solid (yield: 50%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH:10]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)[C:11]#[N:12])=[CH:6][N:5]=2)[CH2:3][CH2:2]1>CO.[Ni]>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH:10]([N:13]3[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15][CH2:14]3)[CH2:11][NH2:12])=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: N#CC(c1cnc(C2CC2)nc1)N1CCC(F)(F)CC1
Agent: [Ni]
Solvent: CO
Product: NCC(c1cnc(C2CC2)nc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.7 %

Procedure:
A mixture of 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile (3.50 g, 126 mmol), Raney Ni (3.50 g) and NH3H2O (10 mL) in MeOH (150 mL) was degassed and purged with argon and H2, then stirred at room temperature under H2 (50 Psi) for 4 hours. The reaction mixture was filtered and concentrated in vacuum to give 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine as a yellow oil (3.10 g), which was used directly for next step without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and 2-(R)-methylpyrrolidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 420 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:12]I>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH3:12])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(Br)cn1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
A solution of this (5-bromo-pyridin-2-yl)-methanol (4.80 g, 23.0 mmol) in DMF (25 mL) was added drop wise over 5 minutes to a slurry of sodium hydride (1.10 g, 27.6 mmol) in DMF (50 mL) at 0° C. under N2. The mixture was stirred for 15 minutes before the drop wise addition of a solution of methyl iodide (1.57 mL, 25.3 mmol) in DMF (25 mL). The mixture was allowed to reach room temperature and was then stirred overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were thoroughly washed with brine, dried over MgSO4 and evaporated to dryness to give the title compound as a yellow oil (4.77 g, 98%) sufficiently pure for the next step.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([NH:13][C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(CC(O)=O)C=CC=CC=1>>[C:7]1([CH2:2][C:1]([N:9]2[CH2:12][CH:11]([NH:13][C:14]3[CH:23]=[CH:22][N:21]=[C:20]4[C:15]=3[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18](=[O:24])[NH:19]4)[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:29]=1
Reactant: O=C(c1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Reactant: O=C(O)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 360 using the amine intermediate from example 366 and phenylacetic acid to provide 368. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COc1ccnc(-c2ccc(Cl)cc2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccnc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)chlorobenzene (500 mg) in sulfuric acid (4 ml) was added fuming nitric acid (0.2 ml) dropwise at 0° C., and the mixture was stirred at 5° C. for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and dried under reduced pressure to give 1-chloro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (601 mg).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C@H:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6][C:7]([O:9][CH3:10])=[O:8].C=O.[C:21](O)(=O)C.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:3]=1[CH2:4][C@H:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:21]2
Reactant: COC(=O)N[C@H](Cc1ccccc1Br)C(=O)OC
Reactant: CC(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1Cc2c(Br)cccc2CN1C(=O)OC
Yield: 91.2 %

Procedure:
Stir a mixture of methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate (29.1 g, 92.10 mmol) and paraformaldehyde (9.13 g, 101.3 mmol) in glacial acetic acid (115 mL, 2.01 mol) and concentrated sulfuric acid (38.4 mL, 719.9 mmol) at room temperature for 7 hours. Partition between water and ethyl acetate. Separate the layers and extract the aqueous layer with ethyl acetate. Combine the ethyl acetate extracts and dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (27.6 g, 84.0 mmol). MS (m/z): 328 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[C:11](=[O:15])[C@H:10]([CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CC(C)C1=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The crude cis:trans mixture of 1-benzyl-3,5-dimethylpiperidin-4-one (typically 6:1 cis:trans) (45 g) was added to a 5% solution of sodium methoxide in methanol (500 mL) and stirred at room temperature for 6 hours. Saturated aqueous ammonium chloride (30 mL) was added and the mixture stirred for a further 30 minutes at room temperature. The mixture was evaporated to dryness and then redissolved in dichloromethane (500 mL). The insoluble solids were filtered off and the solvent was then evaporated to give an enriched mixture 96:4 cis:trans by 1H NMR (quantitative mass recovery). Longer reaction times did not give any further enrichment. If required, pure cis-product could then be obtained by chromatographic purification as described above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]Br.[CH2:17]([N:19](CC)[CH2:20]C)C.CNC>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:19]([CH3:20])[CH3:17]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Agent: CNC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCN(C)C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 97 %

Procedure:
To a solution of (S)-4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester (27.5 g, 93 mmol) in THF (100 mL) in a pressure reaction vessel was added triethylamine (26 mL) and dimethylamine (93 mL of 2.0 M in THF). The reaction vessel was sealed and heated to 60° C. for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in dichloromethane (500 mL). The solution was washed with water (3×200 mL) and brine (200 mL), dried over MgSO4, filtered through Celite and concentrated under reduced pressure. The residue was dried under high vacuum to afford 23.4 g of yellow oil (97% yield).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1>C1COCC1>[CH:2]([C:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:12][C:13]=2[CH:14]=[CH:15][CH:2]=1)([CH2:3][CH3:4])[CH3:15]
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Solvent: C1CCOC1
Product: CCC(C)c1cccc2c1Nc1ccccc1S2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
The stirred solution of 2-chlorophenothiazine (5.02 g, 21.54 mmol) in anhydrous THF (50 mL) was cooled to −78° C. and under argon sec-butyl lithium (77 mL, 108 mmol) was added drop-wise. After all the addition, the resulting orange mixture was stirred at −78° C. for 3 h, then was allowed to warm to room temperature. The reaction was quenched by the slow addition of saturated ammonium chloride, extracted with ethyl acetate (2×400 mL). The combined organics were washed with brine, dried (MgSO4), filtered, concentrated, and purified by chromatography, using ethyl acetate-hexane gradient to afford 1-sec-butyl-10H-phenothiazine. MS (m/z): [M+H]+=256. To the solution of 1-sec-butyl-10H-phenothiazine (1.0 g, 4.14 mmols) in chloroform (30 mL), at 5° C. was added the solution of iodine (3.2 g, 12.61 mmol) in chloroform (125 mL) drop-wise. After the addition the resulting dark mixture was stirred at 5° C. overnight. Product was filtered, washed several times with chloroform, dried to afford the title compound (1.8 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[C:17]([NH2:27])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:28]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:28]=[C:2]([C:33]5[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([NH2:27])=[N:18]1
Reactant: Nc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(-c2ccccc2Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(-c2cn3c(n2)-c2cc(-c4ccc(Cl)cc4)ccc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A mixture of 5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-amine (0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 566 (200 mg, 42.2%). 1H NMR (CDCl3, 400 MHz): δ 8.06 (s, 1H), 7.56-7.37 (m, 10H), 7.03-7.00 (d, J=8.0 Hz, 2H) 4.44 (s, 2H), 4.39 (s, 2H), 4.21 (s, 2H). MS (ESI) m/z 474.08 [M+H+]
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step I. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H, 100%). 1H NMR (200 MHz, CDCl3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, 1H), 6.68 (d, 7 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.1-7.4 (m, 8H), 7.61 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=S)[S:10]C)[CH2:4][O:3]1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=[S:10])[NH:15][NH2:16])[CH2:4][O:3]1
Reactant: NN
Reactant: CSC(=S)NCC1COC(C)(C)O1
Solvent: O
Solvent: CCO
Product: CC1(C)OCC(CNC(=S)NN)O1
Yield: 69.4 %

Procedure:
A mixture of methyl N-(2,2-dimethyl-dioxolan-4-yl-methyl)-dithiocarbamate (23,6 g) prepared according to U.S. Pat. No. 4,064,242, absolute ethanol (500 cc) and hydrazine hydrate (5.6 g) is heated under reflux for 2 hours 30 minutes. It is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in diethyl ether (100 cc). After filtration and drying, 4-(2,2-dimethyl-dioxolan-4-yl-methyl)-thiosemicarbazide (15.2 g) is obtained in the form of a cream-coloured solid melting at 145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([CH:18]=O)([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].[C:23]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][C:10]([C:18]#[CH:23])([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=CC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)c1)(C3)C2
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)c1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To a stirred mixture of 3-chloro-N-(3-formyl-1-adamantyl)benzamide (350 mg, 1.35 mmol) and K2CO3 (370 mg, 2.7 mmol) in methanol (25 mL) under N2 was added dimethyl (1-diazo-2-oxopropyl)phosphonate (310 mg, 1.62 mmol). After stirring at room temperature for three hours, the clear reaction solution was partitioned between ethyl acetate (20 mL) and 5% NaHCO3 (20 mL) and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield 210 mg (61%) of the title compound, 3-chloro-N-(3-ethynyl-1-adamantyl)benzamide, as an off-white solid. ESI-MS m/z: 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.N.CC[N:21](C(C)C)C(C)C>C(Cl)Cl.CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([NH2:21])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3-chloro-5-hydroxybenzoic acid (3.22 mmol), oxalyl chloride (6.5 mmol) and catalytic amount of DMF in DCM was heated at reflux for 2 hrs. (bath temperature at 60° C.). Solvent was evaporated in vacuo and the residue was dissolved in 1,4-dioxane. NH3 (0.5 M in 1,4-dioxane, 1.5 eq.) and DIEA (1.5 eq.) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was transferred to a pressure vessel, followed by the addition of 1 mL of 6 M NH3 in MeOH. The pressure vessel was sealed and heated at 90° C. for 2 hrs. The solvents were evaporated to give a crude product, which was purified by chromatography over silica gel (EtOAc) to yield 0.51 g (57%, theoretical yield 0.896 g) of 3-chloro-5-hydroxybenzamide. LCMS (Cond. A) RT 1.05 min., MH30 172. 1H NMR (500 MHz, CD3OD) δ 7.31 (t, J=1.7 Hz, 1 H), 7.19 (t, J=1.8 Hz, 1 H), 6.94 (t, J=2.1 Hz, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:15]([F:20])[CH:14]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(Br)cc1F

Procedure:
A solution of 1-bromodecane in butanone was added dropwise to a stirred refluxing solution of 4-bromo-2-fluorophenol and potasium carbonate. The stirred mixture was heated under reflux for 24 hr. The potassium carbonate was filtered off and the solvent removed. The product was distilled at 130° C. at 0.05 mmHg.