Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:28][C:27]([F:30])([F:29])[CH2:26]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:31])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])#[CH:40]>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>[F:30][C:27]1([F:29])[CH2:26][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:15]([CH3:31])=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([C:40]#[C:39][Si:41]([CH3:44])([CH3:43])[CH3:42])=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:19]=3)[N:24]=2)[CH2:28]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(Br)ccn12
Reactant: C#C[Si](C)(C)C
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: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C#C[Si](C)(C)C)ccn12
Temperature: 110 °C

Procedure:
7-Bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (42f) (50.0 mg, 0.10 mmol), CuI (3.82 mg, 0.02 mmol), PdCl2(PPh3)2(14.0 mg, 0.02 mmol), triethylamine (20.0 mg, 0.20 mmol) and ethynyltrimethylsilane (20 mg, 0.20 mmol) were mixed in DMF (1 mL) in a 1 mL microwave vial. The vial was capped and heated at 110° C. for 5 minutes under microwave condition. Once complete, the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, concentrated and purified by silica chromatography to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridine-3-carboxamide (52). MS m/z 506.1 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C.[Rh]>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CC(=O)O
Product: N[C@@H](CC1CCCCC1)C(=O)O

Procedure:
116 Grams of L-phenylalanine is dissolved in 1000 ml of 90% acetic acid and hydrogenated over 23 g of 5% rhodium on carbon at 40 psi and 37° C. for 24 hours. The catalyst is removed by filtration, the filtrate is concentrated to dryness under high vacuum, and the residue is crystallized from 2 liters of 15% acetic acid to give L-β-cyclohexylalanine which is represented by the following formula ##STR60## Substitution of an equivalent quantity of L-β-cyclohexylalanine for the L-phenylalanine of Example 1 and substantial repetition of the procedures detailed in Examples 1 through 9 provides methyl L-tyrosyl-D-methionyl-glycyl-L-β-cyclohexylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR61##
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C[CH2:19][N:20](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN>C1COCC1.C(Cl)CCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([NH:20][CH3:19])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1ccc(CCC(=O)O)cc1OCC
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOc1ccc(CCC(=O)NC)cc1OCC
Temperature: 70 °C

Procedure:
To a solution of 0.72 g of 3-(3,4-diethoxy-phenyl)-propionic acid in 10 mL THF were added 1.6 mL of DIPEA, 0.45 g of HOBt, 0.63 g of EDC and 10 mL of MeNH2 (2M in THF). The reaction mixture was heated in a closed vessel overnight at 70° C. Further additions of MeNH2 were done during the next 12 h. The mixture was then concentrated in vacuo, the residue was taken up in sat. aq. NaHCO3 and washed with EtOAc (2×). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC with EtOAc yielded 0.16 g of 3-(3,4-diethoxy-phenyl)-N-methyl-propionamide as solid.
Reaction SMILES: N1C=CC=C([C:7]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)C=1.[Li].[CH3:19][OH:20]>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:19]([C:16]2[C:11]([C:10]([O:9][CH3:7])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:20])[CH:11]=1
Reactant: O=C(OC(=O)c1ccccn1)c1cccnc1
Reactant: CO
Agent: [Li]
Product: COC(=O)c1ncccc1C(=O)c1cccnc1

Procedure:
Synthetic Scheme 6 is yet another method of regiospecific synthesis of the methyl 3-picolinoylpicolinate 7 and 5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one 9. N,N-diethylpicolinamide 14, prepared as in Synthetic Scheme 5, is reacted with 1 equiv of sec-butyl lithium, and, without isolation of the lithiated intermediate, a second equivalent of N,N-diethylpicolinamide 14 is added to the reaction mixture, resulting in the condensation reaction yielding lithium 3-picolinoylpicolinate 16. Lithium 3-picolinoylpicolinate 16 is reacted with methanol to yield the methyl ester, methyl 3-picolinoylpicolinate 7, which is then reacted with hydrazine to yield 5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one 9. The pyridazinone 9 can be converted to the various ketone-Rilyazines 11, and then to the corresponding thione-Rilyazines 13 similarly to the methods shown in Scheme 4.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].C(Cl)(=O)C(Cl)=O.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1CC(O)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.CCCCCC.CCOCC>[CH:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:19]=1[CH2:1][N:2]=[C:3]=[O:4]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C=NCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A drop of dimethylformamide and oxalyl chloride (1 ml) were added to a solution of 2-naphthylacetic acid (840 mg, 4.5 mmol) in methylene chloride (15 ml) at room temperature. This mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was dissolved in acetone (15 ml) and cooled to 0° C. A solution of sodium azide (700 mg, 11 mmol) in water (10 ml) was added. The reaction mixture was stirred for 30 minutes at 5° C. and was then poured into a mixture of ice water (30 ml), ether (40 ml), and hexane (40 ml). The organic phase was separated, washed with brine, dried and concentrated to 5 ml. Chloroform (5 ml) was added to the residue. The resultant solution was added to chloroform (10 ml) at 80° C. dropwise. The mixture was heated at reflux for 1 hour. The solvent was evaporated to give 680 mg of crude product. Purification by chromatography (silica, methylene chloride) gave 342 mg of the desired product as a white solid. IR (neat) 2355 cm−1, 2336 cm−1, 2267 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[S:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].[OH-].[Na+]>O.CO.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:1][O:2][C:3]([C:4]1[C:5]([O:19][CH3:20])=[CH:6][C:7]2[S:18][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:8]=2[CH:9]=1)=[O:21]
Reactant: COC(=O)c1cc(NC(=S)c2ccccc2)ccc1OC
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2nc(-c3ccccc3)sc2cc1OC
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
A 2 liter round bottom flask was charged with 81 grams (246 mmol) potassium ferricyanide in 300 mL of water, the solution was warmed to 55° C. A solution of 14.78 grams (49 mmol) methyl-2-methoxy-5-benzthioamido-benzoate in 200 mL of methanol and 100 mL aqueous sodium hydroxide solution [13.7 gm (343 mmol) NaOH/100 mL] was then added. A yellow precipitate was soon deposited. The mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was partitioned between 1 liter ethyl acetate and 300 mL 3.4 N HCl (aqueous). The organic phase was washed with water and brine solution and then dried over sodium sulfate. After filtration, the filtrate was evaporated and the residue, as a mixture of carboxylates, was used directly in the next step. (affords 12.9 grams crude)
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(CC)C(O)=O)C=CC=CC=1.[Mg+2:25].[Cl-:26].[Cl-]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:26].[Mg+2:25]
Reactant: CCC(C(=O)O)c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCC(C(=O)[O-])c1ccccc1

Procedure:
5.52 g (51.6 mmoles) of the support obtained as already described, are suspended in 300 ml of toluene, operating in a stirred 1,000 ml reactor. 16.9 g (103.2 mmoles) of 2-phenylbutyric acid dissolved in 150 ml of anhydrous toluene (with a molar ratio phenylbutyric acid/MgCl2 equal to 2.0) are slowly added, under stirring, to the suspension obtained, kept at room temperature. At the end of the addition, nitrogen is bubbled in for 3 hours. The residue is filtered on a sintered glass septum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=O)=[CH:5][NH:6]2.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](/[CH:11]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:5][NH:6]2
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2cccc(Cl)c12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])/C=C/c1c[nH]c2cccc(Cl)c12
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-chloroindole-3-carbaldehyde (314 mg, 1.75 mmol) and ammonium acetate (404 mg, 5.25 mmol) in nitromethane (6 mL) was stirred at 100° C. for 20 min. The reaction mixture was cooled, diluted with water and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silicagel column chromatography (50-100% EtOAc/heptane) to give compound B19-1 (224 mg, 58%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH2:11][OH:12])[NH:8][C:7]=12>[O-2].[Mn+4].[O-2].ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][C:7]=12
Reactant: OCc1cc2ccnc(Cl)c2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2ccnc(Cl)c2[nH]1
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (Example 1) (2.81 g, 15.4 mmol), manganese(IV)oxide (16 g) and dichloromethane (250 mL) was stirred under an atmosphere of nitrogen for 16 h. The mixture was filtered through a pad of diatomaceous earth, washing generously with hot acetone. Evaporation of the solvents provided 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (2.40 g, 13.3 mmol, 84%) as a mixture of aldehyde and aldehyde hydrate: 1H NMR (300 MHz, CD3OD) δ5.79 (1H, s), 6.65 (1H, s), 7.44 (1H, s), 7.53 (1H, d, J=5.5 Hz), 7.72 (1H, d, J=5.5 Hz), 7.85 (1H, d, J=5.5 Hz), 7.99 (1H, d, J=5.5 Hz), 10.02 (1H, s); ESI MS m/z 181 [C8H5ClN2O+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([Cl:10])=[C:4](C)[C:5]([Cl:8])=[CH:6][CH:7]=1.F[C:12]1C=C(C)C=CC=1.FC1C=C(C)C(Cl)=CC=1.FC1C=C(C)C=CC=1Cl>>[F:1][C:2]1[CH:7]=[C:6]([CH3:12])[C:5]([Cl:8])=[CH:4][C:3]=1[Cl:10]
Reactant: Cc1cccc(F)c1
Reactant: Cc1c(Cl)ccc(F)c1Cl
Agent: Cc1cc(F)ccc1Cl
Agent: Cc1ccc(Cl)c(F)c1
Product: Cc1cc(F)c(Cl)cc1Cl

Procedure:
3-Fluoro-4,6-dichlorotoluene is prepared with reduced formation of 3-fluoro-2,6-dichlorotoluene by chlorinating 3-fluorotoluene in the presence of a catalyst system to give a mixture containing 3-fluoro-6-chlorotoluene and 3-fluoro-4-chlorotoluene and chlorinating this in the presence of another catalyst system to give 3-fluoro-4,6-dichlorotoluene.
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][NH:12]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[BrH:16]>O>[BrH:16].[OH:2][C:3]1[C:15]2[CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][NH:12]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C[C@@H]1NCC[C@@H]1C2
Agent: Br
Solvent: O
Product: Oc1cccc2c1C[C@@H]1NCC[C@@H]1C2
Yield: 95 %

Procedure:
0.55 g (2.7 mmol) of cis-(±)-8-methoxy-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (10b) are added to 6 mL of water and 12 mL of conc. hydrobromic acid and refluxed for 20 h . Then the mixture is concentrated by evaporation in vacuo, the residue is taken up again in 10 mL of ethanol and the solvent is eliminated again in vacuo. 0.69 g (95%) of the desired product are obtained as the hydrobromide.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].O[Li].O.Cl.C(Cl)CCl.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:26]1([NH:25][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)CCCCCCC(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCCCC(=O)C(F)(F)F)Nc1ccccc1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of ester 71 (300 mg, 1.25 mmol) in THF (18 mL) was added a solution of LiOH.H2O (262 mg, 6.24 mmol) in H2O (6 mL) and the suspension was stirred overnight. The mixture was then acidified with HCl (1 N) to pH 2 and then extracted with EtOAc (3×15 mL). The extracts were combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a white solid (211 mg, 0.93 mmol, 75%). To a solution of this acid (109 mg, 0.48 mmol), EDC (111 mg, 0.58 mmol), and DMAP (5 mg) in CH2Cl2 (5 mL) was added aniline (49 μL, 0.53 mmol) and the reaction allowed to proceed overnight. The solution was partitioned between H2O (5 mL) and EtOAc (10 mL). The layers were separated, and the aqueous phase extracted with EtOAc (3×5 mL). The organic portions were combined, washed with brine, dried over MgSO4, and filtered. Evaporation under reduced pressure left a solid which was purified by preparative TLC (30% EtOAc/hexanes) with isolation of the least polar band by EtOAc extraction. The extract was concentrated to give 72 as a yellowish solid (92 mg, 0.31 mmol, 65%). TLC Rf 0.48 (50% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) δ 7.51 (d, 2H), 7.32 (t, 2H), 7.10 (t, 1H), 2.72 (t, 2H), 2.36 (t, 2H), 1.72 (m, 4H), 1.40 (m, 4H); 19F NMR (? MHz, CDCl3) −78.40 (s, 3F); MS (APCI+) calcd for C15H19F3NO2 301, found 325 [M+Na]+.
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.Cl.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)=[CH:34][CH:33]=1.[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69]([N:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=3)=[CH:43][N:42]=2)[CH2:49][CH2:48]1)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Clc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 80.9 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine dihydrochloride (0.228 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one(0.295 g), to yield the title compound as a yellow solid (0.325 g, 81%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][NH2:26]>CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:26][CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: CN
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Solvent: CN(C)C=O
Product: CNc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A solution of 1 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 4 ml of N,N-dimethylformamide was cooled in an ice bath and saturated with methylamine. After 64 hr at room temperature, 50 ml of ice water was added and the reaction was filtered. The precipitate was partitioned between 50 ml of dichloromethane and 50 ml of water, and the organic layer was washed with 25 ml of brine solution, dried and evaporated to dryness. The oil was crystallized from ether and then recrystallized from dichloromethane/ether and then from methanol to give the end product as white prisms, mp 172°-179°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1ccc2c(nnn2CC2CCC2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cccnc1Oc1ccc2c(nnn2CC2CCC2)c1Br

Procedure:
A mixture of 4-bromo-1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-5, 25 mg, 0.12 mmol, 1 equiv), 2-chloropyridine-3-carbonitrile (76 mg, 0.62 mmol, 5.0 equiv) and potassium carbonate (34 mg, 0.25 mmol, 5.0 equiv) in acetonitrile (3 mL) was irradiated at 170° C. in microwave reactor for 10 min. The mixture was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give 2-{[4-bromo-1-(cyclobutylmethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbonitrile (1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.26 (dd, 1H, J=4.9, 1.8 Hz), 8.08 (dd, 1H, J=7.3, 1.8 Hz), 7.54 (d, 1H, J=8.8 Hz), 7.39 (d, 1H, J=8.8 Hz), 7.15 (dd, 1H, J=7.3, 4.9 Hz), 4.66 (d, 2H, J=7.3 Hz), 3.00 (p, 1H, J=7.3 Hz), 2.11 (m, 2H), 1.92 (m, 4H) ppm. LRMS m/z (M+H) 386.0 found, 386.0 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[OH:19][CH:20]1[CH2:23][NH:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:19][CH:20]1[CH2:23][N:22]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[CH2:21]1
Reactant: OC1CNC1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic acid (30 mg, 0.12 mmol), 3-hydroxyazetidine hydrochloride (13 mg, 0.12 mmol) and HOBt (16 mg, 0.12 mmol) were dissolved in DMF (3 ml) and DIPEA (43 μl, 0.25 mmol). After 5 min, EDCI (30 mg, 0.15 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 ml) and DCM (3×20 ml). The combined organics were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol:dichloromethane (1:24) to give the title compound as a white solid. δH (CD3OD): 4.06–4.15 (3H, m), 4.40–4.46 (1H, m), 4.55–4.63 (1H, m), 4.77–4.94 (2H, m), 7.14 (1H, s), 7.71 (1H, s), 8.62 (1H, s); RT=2.82 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]([C:8]([CH3:7])=[O:9])[C:3](=[O:2])[CH3:12])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(c(N(C(C)=O)C(C)=O)c1)CC(C)O2

Procedure:
A reaction mixture consisting of 2.4 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine, 10 cc of acetic anhydride and one drop of pyridine is heated to 130°-140° C. for 90 minutes. After cooling and evaporating the excess of acetic anhydride, the residue is distilled under reduced pressure yielding 2.4 grams (69 percent of theoretical) of the compound of the title. B.p./0.4 mmHg 160° C. The distillate which solidifies is crystallized from ethyl ether-petroleum ether. M.p. 56°-57° C.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH:7](C(C2C=CC(C)=CC=2)=O)[OH:8])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:26]#[C:27][Si](C)(C)C)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.[Na]>C[O-].[Na+].CO>[C:26]([C:24]1[C:22](=[O:23])[NH:21][C:19](=[O:20])[N:18]([CH:25]=1)[C@@H:4]1[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]1)#[CH:27]
Reactant: Cc1ccc(C(=O)C(O)[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product of Stage c), in 0.2M sodium methoxide in methanol (freshly prepared from sodium and methanol) is stirred at room temperature for 3.0 hr. then neutralized by portionwise addition of Dowex 50 (H+) ion exchange resin. The resin is filtered off and washed well with methanol. The filtrate is evaporated to dryness and the residue partitioned between water and ether. The aqueous layer is washed with ether then evaporated to dryness, the residue triturated with ethanol and the solid filtered and washed with ether to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].C([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(OC(C)(C)C)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred solution of 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (Example 143, step A) (0.53 g, 2.1 mmol) and 1-BOC-4-piperidone (2.1 g, 10.6 mmol) in DCE (21 mL) was added HOAc (0.25 g, 4.2 mmol) followed by addition of sodium triacetoxyborohydride (2.2 g, 10.6 mmol). The reaction was stirred under N2 at rt for 3 h. The reaction was quenched with aqueous (saturated) NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. The desired fractions were concentrated under vacuum. The residue was dissolved and stirred in a 20% solution of TFA/DCM (50 mL) for approximately 2 h at rt. The mixture was concentrated under vacuum. The residue was dissolved in DCM and neutralized with aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. The desired fractions were concentrated under vacuum to give the title compound of step A (560 mg, 1.68 mmol, 79%) as a yellow solid. MS (ESI): 335 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Cl)c1Cl

Procedure:
2,3-Dichlorobenzaldehyde is cleanly reduced using an alkaline solution of sodium borohydride in methanol to afford 2,3-dichlorobenzyl alcohol.