Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](Cl)=[O:36])=[CH:34][C:29]=2[O:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:35]([C:33]3[CH:32]=[CH:31][C:30]4[O:26][CH2:27][O:28][C:29]=4[CH:34]=3)=[O:36])=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, 3-(aminomethyl)-7-chloro-2-(oxazol-2-yl)-1-phenylquinolin-4(1H)-one (intermediate A) (20 mg, 0.057 mmol), benzo[d][1,3]dioxole-5-carbonyl chloride (12 mg, 0.065 mmol) and N,N-(dimethylamino)pyridine (DMAP) (1.0 mg, 0.085 mmol) were combined with methylene chloride (1.5 mL) to give a brown solution. N,N-diisopropylethylamine (37 mg, 0.050 mL, 0.28 mmol) was added. The reaction mixture was stirred overnight at room temperature. In the morning, LC/MS indicated complete conversion to the desired product. The reaction mixture was diluted with 10 mL methylene chloride, then the organic solution was washed with water. The organic phase was dried over Na2SO4, filtered, then concentrated over silica gel. The silica gel-supported crude product was loaded onto a 25 gram SiliCycle column. Flash chromatography (50% ethyl acetate-hexanes ramped to 75% ethyl acetate-hexanes) afforded benzo[1,3]dioxole-5-carboxylic acid (7-chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide as a brown oil. 1H NMR (300 MHz, chloroform-d) δ ppm 8.36 (d, J=8.67 Hz, 1H) 7.50 (d, J=0.94 Hz, 1H) 7.34-7.42 (m, 4H) 7.30 (dd, J=8.67, 1.88 Hz, 1H) 7.15-7.26 (m, 6H) 7.05 (d, J=0.94 Hz, 1H) 6.77 (d, J=1.88 Hz, 1H) 6.70 (d, J=8.10 Hz, 1H) 5.91 (s, 2H) 4.37 (s, 2H). MS calcd. for C27H18ClN3O5 [(M+H)+] 499.9, obsd. 500.0.
Reaction SMILES: C(NCC(C1C=CC=C(OC)C=1)O)C1C=CC=CC=1.ClCC(Cl)=O.[CH2:25]([N:32]([CH2:37][CH:38]([OH:47])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[C:33](=[O:36])[CH2:34]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[K+]>ClCCl.C(O)(C)C>[CH2:25]([N:32]1[CH2:37][CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=2)[O:47][CH2:34][C:33]1=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(C(O)CN(Cc2ccccc2)C(=O)CCl)c1
Agent: COc1cccc(C(O)CNCc2ccccc2)c1
Agent: O=C(Cl)CCl
Agent: [K+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cccc(C2CN(Cc3ccccc3)C(=O)CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
In a 250 mL round-bottomed flask, 2-(benzylamino)-1-(3-methoxyphenyl)ethanol (1.92 g, 7.46 mmol,) and TEA (831 mg, 1.14 ml, 8.21 mmol) were combined with dichloromethane (60 ml) to give a colorless solution. To this chloroacetyl chloride (927 mg, 657 μl, 8.21 mmol) in 10 mL dichloromethane was added dropwise at 0° C. After 1 h at 0° C. the reaction mixture was quenched with 1M aqueous HCl. The layers were separated, the aqueous layer extracted with dichloromethane. The combined organic layers were washed with 5% aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude intermediate N-benzyl-2-chloro-N-[2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-acetamide (2.61 g, 7.82 mmol) was combined with isopropanol (50 ml) to give a light yellow solution. KOH (526 mg, 9.38 mmol) was added and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was partitioned between ethyl acetate and 0.5M aqueous HCl. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 4-benzyl-6-(3-methoxyphenyl)-morpholin-3-one (2.3 g, 99%) which was directly used for next step without further purification. (M+H)+=298 m/e.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Cl:21]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from [tert-butoxycarbonyl-(4-iodo-pyridin-3-yl)-amino]-acetic acid methyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic purification. Colorless oil (49%). MS (ESI): m/z=377.126 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[S:6]1[CH2:12][C:10](=[O:11])[NH:9][C:7]1=S.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][NH:5][C:7]2[S:6][CH2:12][C:10](=[O:11])[N:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1CSC(=S)N1
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCC2CC2)=N1

Procedure:
Similar procedure as described in example 67(a) was used, starting from cyclopropylmethylamine, rhodanine (2-thioxo-4-thiazolidinone), mercuric chloride and DIEA to give 2-cyclopropylmethylamino-thiazol-4-one. LC-MS m/e 171 (MH+).
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(OCC)(=O)C>O1CCCC1>[C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N+:25]3([CH3:24])[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1
Reactant: O=C(O)C1=C(CCl)CS[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)c4ccccc4)[C@H]3SC2)CCCC1
Reaction time: 2 h

Procedure:
To a solution of 7-benzoylamino-3-chloromethyl-3-cephem-4-carboxylic acid (14 g) in tetrahydrofuran (280 ml) was added dropwise 1-methylpyrrolidine (16.9 g) over a period of 10 minutes at 10° C. After the mixture was stirred for two hours at 25°~28° C., ethyl acetate (280 ml) was added thereto. The precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether, dried over phosphorus pentoxide to give 7-benzoylamino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][C:32]1[CH:33]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>CC(O)C>[N:11]1([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:31][C:32]3[CH:33]=[C:34]([S:38]([NH2:41])(=[O:39])=[O:40])[CH:35]=[CH:36][CH:37]=3)[N:10]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: CS(=O)(=O)c1nccc(-n2ncc3ccccc32)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: NS(=O)(=O)c1cccc(Nc2nccc(-n3ncc4ccccc43)n2)c1

Procedure:
A solution of 1-(2-methylsulfonyl-pyrimidin-4-yl)-1H-indazole (100 mg, 0.36 mmol) and p-toluenesulfonic acid (139 mg, 0.73 mmol) in i-PrOH (4 ml) was treated with 3-aminobenzene-sulfonamide (251 mg, 1.46 mmol) in a microwave synthesizer at 150° C. for 20 min. The mixture was partitioned between water and ethyl acetate, the organic layer separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was absorbed on silica gel and purified by flash chromatography (EtOAc/hexane, gradient from 30:70 to 50:50) to afford the title compound. This residue was triturated with aqueous NaOH (1 M), the solid collected by filtration, washed with water and dried under vacuum to afford 3-(4-indazol-1-ylpyrimidin-2-ylamino)-benzenesulfonamide (50 mg, 37% yield). MS=367 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C1COCC1.C([O-])(O)=O.[Na+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(OCC)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([C@H:2]([NH:1][C:23](=[O:39])[O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:3][OH:4])[CH:10]=[C:9]([I:11])[CH:8]=1
Reactant: N[C@H](CO)c1cc(F)cc(I)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H](CO)c1cc(F)cc(I)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 75.4 %

Procedure:
To (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol (4500 mg, 14.17 mmol) was added THF (Volume: 40 mL, Ratio: 2.67) and water (Volume: 15 mL, Ratio: 1.000), followed by NaHCO3 (4762 mg, 56.7 mmol). The mixture was stirred for 2 minutes then cooled to 0° C. in an ice bath. To the reaction was added (9H-fluoren-9-yl)methyl carbonochloridate (5499 mg, 21.26 mmol) and the reaction was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 60 minutes, before conducting LCMS. Ethyl acetate was added to the crude reaction mixture. The mixture was washed with water (2×), saturated salt solution, dried sodium sulfate, filtered and concentrated to residue. The crude product was purified by silica gel chromatography using a 300 g column (solid load) eluting from 0-60% ethyl acetate in heptane. The desired fractions were concentrated to constant mass to give as white solid 5375 mg of the desired product as free base used as is, (73% yield). LCMS (m/z): 504.1 (MH+), 1.05 min. 1H NMR (<cd3od>) d: 7.78 (d, J=7.4 Hz, 2H), 7.64 (d, J=7.2 Hz, 2H), 7.53 (s, 1H), 7.33-7.43 (m, 3H), 7.25-7.33 (m, 2H), 7.07 (d, J=9.2 Hz, 1H), 4.64 (t, J=5.9 Hz, 1H), 4.31-4.46 (m, 2H), 4.21 (t, J=6.3 Hz, 1H), 3.66 (d, J=3.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28]>O1CCOCC1.Cl>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)[C:27]([NH2:28])=[NH:26]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 71 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and cyanamide in dioxane/hydrogen chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(OC1C(=C=O)C(O)C=CC=1OCC)C.C(O)(=O)C>>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(=CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: CCOC1=C(OCC)C(=C=O)C(O)C=C1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate, melting point 125°-126° C., which in turn was prepared from (2-piperidino-phenyl)-isobutyl-ketimine and 3-ethoxy-4-ethoxy-carbonyl-phenol-acetic acid analogous to Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][CH:34]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 576.9 (M+H)+.
Reaction SMILES: ClC1N=C2C(C=[CH:7][C:8]([N:12]3[CH:20](OC(OC4C=CC=CC=4)=O)[C:19]4[C:14](=CC=[CH:17][CH:18]=4)[C:13]3=O)=N2)=CC=1.C(#[N:34])C>>[CH2:20]([N:12]1[CH2:8][CH2:7][NH:34][CH2:14][CH2:13]1)[CH:19]=[CH:18][CH3:17]
Reactant: CC#N
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Product: CC=CCN1CCNCC1

Procedure:
Following the procedure of Example 36 but starting from 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-1-isoindolinone (4.32 g.) and 1-(but-2-en-1-yl)-piperazine (7 g.) in acetonitrile (25 cc.), 3-[4-(but-2-en-1-yl)-1-piperazinyl]-carbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (1.95 g.) melting at 190° C is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[OH-].[K+].C([O:15][C:16](=[O:21])[C:17](=O)[CH2:18]Br)C.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:10])[CH2:3][C:4](=[O:9])[C:5]2[C:17]([C:16]([OH:21])=[O:15])=[CH:18][O:8][C:6]=2[CH2:7]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC(=O)c2c(C(=O)O)coc2C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5,5-Dimethyl-1,3-cyclohexandione is dissolved in 15 ml of methanol and cooled to 0° C. A solution of KOH (2 g, 35.7 mmol) in 15 ml of methanol is added drop wise. A solution of 3-bromo-2-oxo-propionic acid ethyl ester (4.7 ml, 37.5 mmol) in 15 ml of methanol is added drop wise. The mixture is allowed to warm up to room temperature and is stirred for 16 h. Then 15 ml of a 45% aqueous sodium hydroxide solution is added. After additional 4 h at room temperature, 25 ml of concentrated HCl is added. Methanol is evaporated slowly under reduced pressure whereas the product precipitates as light crystals. The product is filtrated off and washed with water.
Reaction SMILES: [CH:1]1[C:11]([Br:12])=[CH:10][C:9]2[C:3](=[N:4][C:5]([NH:7][N+:8]=2[O-:13])=O)[CH:2]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:12][C:11]1[CH:1]=[CH:2][C:3]2[N:4]=[C:5]([Cl:16])[N:7]=[N+:8]([O-:13])[C:9]=2[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc2ccc(Br)cc2[n+]([O-])[nH]1
Product: [O-][n+]1nc(Cl)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of 7-bromo-1-oxy-benzo[1,2,4]triazin-3-ol (11 g, 46 mmol) in POCl3 (50 mL) was heated under reflux for 16 h, cooled to rt, poured into ice-water and stirred for 30 min. The mixture was filtered, washed with water and dried to afford 7-Bromo-3-chloro-benzo[1,2,4]triazine 1-oxide (5 g, 42%) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[NH:22][C:23]([NH2:25])=[O:24]>C(O)C.[Ni]>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=[N:16][NH:22][C:23]([NH2:25])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCOc1cccc(CN2CCCCC2)c1
Reactant: NNC(N)=O
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: NC(=O)NN=CCCCOc1cccc(CN2CCCCC2)c1
Yield: 76.4 %

Procedure:
A solution of 4-[3-(1-piperidinylmethyl)phenoxy]butannitrile (51.6 g) sodium acetate (73.8 g) and semicarbazide hydrochloride (77.6 g) in 50% aqueous ethanol (1 L) was hydrogenated over Raney Nickel (50 g). The catalyst was removed by filtration. The filtrate was partially evaporated, made basic with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated to leave an oil which was purified by column chromatography to give the title compound as a pale yellow oil (48.6 g); tlc System B, Rf 0.8.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl.[NH2:20]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([C:13]#[N:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: NO
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(C#N)c1Cl
Temperature: 100 °C

Procedure:
A solution of the compound of Example 223 (0.28 g, 1.0 mmol) and hydroxylamine hydrochloride (0.12 g, 1.7 mmol) in pyridine (10 mL) was stirred at RT for 2 h. Acetic anhydride (0.75 mL, 8.0 mmol) was added and the solution was heated at 100° C. for 1.5 h. The mixture was concentrated, water added and the mixture extracted with ether. The organic layers were washed with 0.5N HCl, sat NaHCO3, brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by recrystallization from ethyl acetate/hexanes to afford 0.21 g of white needles (74%). m.p. 111°-112° C.
Reaction SMILES: Br.Br[C:3]1[O:7][C:6]([C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:3]2[O:7][C:6]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncccc1-c1ccc(Br)o1
Agent: Br
Product: Nc1ncccc1-c1ccc(-c2ccccc2)o1

Procedure:
In the same manner as in Example 14, step A, the title compound (1.19 g) was obtained as a yellow solid from 3-(5-bromofuran-2-yl)pyridin-2-amine hydrobromide and phenylboronic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[CH3:7][C:8]([CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][CH2:11]1)=[O:9]>>[CH3:16][C:14]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH:10]([C:8]([OH:9])([CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH3:7])[CH2:15]1
Reactant: CC(C)CCBr
Reactant: CC(=O)C1CCCC(C)(C)C1
Product: CC(C)CCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 3-methyl-1-bromobutane replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: N[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:11]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:19].N([O-])=O.[Na+]>O>[Cl:19][C:2]1[CH:7]=[CH:8][C:9]2[S:10][C:11]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc2c(c1)SC=Cc1c(N)cccc1-2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Reaction time: 0.5 h

Procedure:
1 G. 8-amino-3-cyanodibenzothiepin is suspended in 16 cc. concentrated hydrochloric acid and 5 cc. of water. The suspension is maintained at a temperature between 0° and 5° C. and 300 mg. sodium nitrite in 2 cc. of cold water is added slowly. The reaction mixture is stirred for 1/2 hour. A mixture of 400 mg. cuprous chloride and 700 mg. cupric chloride dihydrate is then added slowly. After the evolution of nitrogen has subsided, the reaction mixture is stirred at room temperature for 20 minutes, water added and the reaction mixture extracted with chloroform, dried over sodium sulfate and evaporated to dryness to yield 995 mg. (92%) of the pure chloro derivative, m.p. 207°-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:3]=1.C(O)(C(F)(F)F)=O.[Cl:23][C:24]1[N:25]=[C:26](Cl)[C:27]2[CH2:33][N:32]([CH3:34])[CH2:31][CH:30]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:28]=2[N:29]=1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:26]2[C:27]3[CH2:33][N:32]([CH3:34])[CH2:31][CH:30]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:28]=3[N:29]=[C:24]([Cl:23])[N:25]=2)[CH:3]=1
Reactant: N#Cc1ccc(N)cc1OCCCCN
Reactant: CN1Cc2c(Cl)nc(Cl)nc2C(c2ccc(F)cc2)C1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(NCCCCOc3cc(N)ccc3C#N)nc(Cl)nc2C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.72 %

Procedure:
A mixture of 4-amino-2-(4-aminobutoxy)benzonitrile, 2 TFA salt (Preparation X, 23.32 mg, 0.054 mmol), 2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Preparation V, 14 mg, 0.045 mmol) and DIEA (39.2 μL, 0.224 mmol) in acetonitrile (224 μL) was stirred at rt for 4 h. The crude product was purified by Prep-HPLC to obtain 4-amino-2-(4-((2-chloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)butoxy)benzonitrile, (5.0 mg, 15.72% yield). LC-MS (M+Na)+=481.2. 1H NMR (500 MHz, methanol-d4) δ 7.26-7.18 (m, 3H), 7.16-7.08 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 6.28 (dd, J=8.5, 1.9 Hz, 1H), 4.45 (dd, J=10.5, 6.3 Hz, 1H), 4.30 (d, J=11.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.89 (dd, J=12.4, 6.3 Hz, 1H), 3.70-3.52 (m, 3H), 3.18-3.08 (m, 3H), 2.01-1.80 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12)=[O:2].[BH4-].[Na+].[OH-].[Na+]>O>[OH:2][CH2:1][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12
Reactant: O=Cc1cccc2c1CC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCc1cccc2c1CC2

Procedure:
4-Formylbenzocyclobutene is reduced with sodium borohydride in water, containing 1% by weight of sodium hydroxide. 4-Hydroxymethylbenzocyclobutene is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O>COCCOC.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>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1ccc(CO)cc1
Temperature: 80 °C
Yield: 26.3 %

Procedure:
Nitrogen was bubbled through a mixture of 1-bromo-4-chloro-2-nitro-benzene (1.25 g, 5.3 mmol), bis(triphenylphosphine)palladium(II) chloride (90 mg, 0.13 mmol) and potassium phosphate tribasic (4.2 g, 19.7 mmol) in anhydrous 1,2-dimethoxyethane (30 mL) for 15 minutes. A solution of 4-(hydroxymethyl)phenylboronic acid (0.8 g, 5.3 mmol) in anhydrous 1,2-dimethoxyethane (1.5 mL) was added and the resulting mixture was heated at 80° C. overnight. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 70/30) to give 0.367 g of (4′-chloro-2′-nitro-biphenyl-4-yl)-methanol as a solid.