Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])=[CH:26][CH:25]=2)[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH2:1]([O:8][C:9]([C:11]1([N:16]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:53][N:52]=[N:51][N:37]=3)=[CH:26][CH:25]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)OCc2ccccc2)CCCC1

Procedure:
A mixture of 3.2 g (6.5 mmol) of N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine, 3.3 g (9.8 mmol) of tributyltin azide and 35 ml of o-xylene is heated to reflux for 24 hours. Working-up of the mixture in a manner analogous to that described in Example 23 yields the N-(1-benzyloxycarbonylcyclopentyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in the form of a yellow oil [Rf : 0.37 (system S2)], which can be used for further reactions in crude form.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=O>>[F:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,4-difluorobenzoic acid: MS (APCl): m/z 405 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:1][C@@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NC[C@@H](O)c1ccccc1)c1ccc(Cl)nn1
Product: O=C(NC[C@@H](O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use (S)-6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (64.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.28, 8.05, 7.76, 7.64, 7.58, 7.44-7.32, 7.29, 7.00, 4.96, 4.08, 3.92-3.68, 3.61, 3.36. MS (ES+) m/z 500 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>>[C:10]([N:9]=[C:12]([NH2:13])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])#[N:11]
Reactant: Nc1ccccc1F
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: N#CN=C(N)Nc1ccccc1F

Procedure:
A solution of 2-fluoroaniline and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:35]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:35])=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)O
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@]1(OC(=O)c2ccco2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (6.20 g) is dissolved in ethyl acetate (100 mL). DBU (2.20 g) and dimethyl sulphate (1.83 g) are added sequentially. The reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords furan-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 3.75 (3H, s), 6.30 (1H, dd), 6.45 (1H, d), 6.55 (2H, m), 7.15 (1H, d), 7.60 (1H, d).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3ccc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-quinoline. MS (ESI) mass calcd. for C28H25N3O, 419.53; m/z found, 420.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.CN(C)[CH:26]=[CH:27][C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O.[ClH:37]>C(O)(=O)C.C(O)(C)C>[ClH:37].[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[C:6]([C:7]#[N:8])=[C:2]4[N:1]=[CH:26][CH:27]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[N:3]4[N:4]=3)[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(CN2CCN(c3[nH]nc(N)c3C#N)CC2)c1
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cccc(CN2CCN(c3nn4c(-c5cccnc5)ccnc4c3C#N)CC2)c1

Procedure:
A mixture of 5.0 g of 3-amino-5-[4-[(3-methoxyphenyl)methyl]-1-piperazinyl]-1H-pyrazole-4-carbonitrile (prepared as described in Example 19) and 2.9 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (U.S. Pat. No. 4,281,000, Example 1) in 25 ml of glacial acetic acid was heated at reflux for 3 hours. The work procedure of Example 21 was followed to obtain a gummy solid. The solid was dissolved in isopropanol and was treated with 20 ml of 2.9N ethanolic hydrochloric acid. The yellow precipitate formed was collected by filtration, washed with isopropanol and dried in vacuo. The product was recrystallized from ethanol/water and gave 2.5 g of the desired product as a yellow solid, mp >250° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28]O)[CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: OCCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.206 g (1.5 mmol) of 3-(pyridin-3-yl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:1) to obtain the product as a oil (0.39 g).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Cl:1][C:2]1[N:11]([CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1Cn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
8-Chlorotheophylline and 2-methylbenzyl bromide were reacted and purified as described in the General procedure C, step A, to afford 85A as white crystals in 86%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:28][CH2:27][N:26]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:25]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1ccc(C2CCNC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)C2)cc1
Temperature: 70 °C
Yield: 56.3 %

Procedure:
A solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (50 mg, 0.22 mmol) in ethanol (1 mL) was added to 3-(4-methoxyphenyl)pyrrolidine hydrochloride (71 mg, 0.33 mmol). The reaction mixture was treated with DIPEA (86 mg, 0.66 mmol) and the mixture was heated at 70° C. for 16 hours. The reaction mixture was evaporated to leave an involatile residue that was purified by preparative reverse phase chromatography to give 6-[3-(4-methoxyphenyl)pyrrolidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (45 mg, 55%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.B(F)(F)F.CCOCC>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[N:16][S:13]([CH2:12][CH2:11][Si:10]([CH3:18])([CH3:17])[CH3:9])(=[O:15])=[O:14])[CH:4]=1
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Reactant: O=Cc1cccnc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)N=Cc1cccnc1
Yield: 102.2 %

Procedure:
To a solution of 3-formylpyridine (0.228 mL, 2.42 mmol) and 2-(trimethylsilyl)ethanesulfonamide (0.438 g, 2.42 mmol) in toluene (30 mL) was added boron trifluoride etherate (0.02 mL, 0.15 mmol) under Ar. The mixture was heated at reflux for 20 hours using a Dean-Stark trap. After cooling, 10% aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness to under reduced pressure obtain crude 2-trimethylsilyl-ethanesulfonic acid pyridin-3-ylmethyleneamide (669 mg), which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:18][O:17]1.O>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([OH:17])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH2:18][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 80 °C

Procedure:
Sodium hydride (50% suspension in oil--2.23 g) was suspended in dimethylformamide (30 ml) under an atmosphere of argon, and cooled in a water bath while imidazole (3.2 g) was added in portions. A solution of 2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane (6.4 g) in dimethylformamide (30 ml) was added, and the mixture was heated at 80° C. for 2 hours. The mixture was cooled, poured into water (200 ml) and extracted with methylene dichloride. The organic extract was washed with water twice and with brine twice, dried over sodium sulphate and filtered. The solvent was evaporated under reduced pressure, and the residue was chromatographed on a K60 silica column, eluting with 0 to 7% of methanol in methylene dichloride, to give 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-3-(1,2,4-triazol-1-yl)-2-propanol, m.p. 169°-170° C.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)=[O:31]>ClCCl.O>[OH:38][C:34]1[CH:33]=[C:32]([C:30](=[O:31])[CH2:29][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)Nc1ccc(CCOCCCCCCNCc2ccccc2)cc1
Reactant: O=C(CBr)c1cccc(O)c1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(CCOCCCCCCN(CC(=O)c2cccc(O)c2)Cc2ccccc2)cc1
Yield: 52.1 %

Procedure:
A solution of N-[4-[2-[[6-[(phenylmethyl)amino]hexyl]oxy]ethyl]phenyl]acetamide (1 g), 2-bromo-1-(3-hydroxyphenyl)ethanone (0.61 g) and DEA (0.8 g) in dichloromethane (20 ml) was stirred under nitrogen for 18 h, diluted with water (20 ml), and extracted with dichloromethane (25 ml). The organic layer was washed with 8% sodium bicarbonate solution (20 ml), dried and evaporated in vacuo to give the title compound as a yellow oil (0.71 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I>[NH2:13][CH2:12][CH2:11][NH:14][C:2]1[N:3]=[C:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[N:6]=1
Reactant: CN(C)c1nc(Br)nn1C
Reactant: NCCN
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NCCN)nn1C
Temperature: 80 °C

Procedure:
5-Bromo-N,N,2-trimethyl-1,2,4-triazol-3-amine (103 mg, 0.5 mmol) and copper (I) iodide (4.8 mg, 0.025 mmol) were placed in a sealed microwave vial and flushed with argon. Then ethane-1,2-diamine (1.5 ml, 22 mmol) and triethylamine (140 μL, 1 mmol) were added via siringe. The reaction mixture was heated in a microwave oven at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr and the filtrate was concentrated under reduced pressure to give 97 mg (quantitative) MS(ESI) m/z=185.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: Cc1c(C(=O)O)cc(O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Yield: 80 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-3-nitrobenzoic acid (3.50 g, 17.8 mmol) in methanol (40 mL), was added thionyl chloride (3.9 mL, 53 mmol) at 0° C. The mixture was heated under reflux for 3 hours and concentrated under reduced pressure. Aqueous sodium bicarbonate was added to the residue which was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (3.0 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[NH2:8].[O:19]1[C:23]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]([C:29](O)=O)=[N:20]1>>[Cl:1][C:2]1[C:7]2[NH:8][C:29]([C:21]3[CH2:22][C:23]4([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[O:19][N:20]=3)=[N:9][C:6]=2[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1
Reactant: Nc1c(Cl)cc(-c2ccccc2F)cc1[N+](=O)[O-]
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Product: Fc1ccccc1-c1cc(Cl)c2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 3-chloro-2′-fluoro-5-nitro-biphenyl-4-ylamine (as prepared in the previous step) and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedures described in Example 16, steps B and C. 1H-NMR (400 MHz, d4-MeOH) δ: 7.64 (br. s., 1H), 7.52 (td, J=7.8, 1.8 Hz, 1H), 7.48 (s, 1H), 7.35-7.43 (m, 1H), 7.27 (td, J=7.5, 1.3 Hz, 1H), 7.21 (ddd, J=11.1, 8.2, 1.1 Hz, 1H), 1.71-1.88 (m, 6H), 1.48-1.66 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][CH2:4]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Yield: 89 %

Procedure:
To a solution of 4-hydroxypiperidine (5.10 g, 50 mmoles) and triethylamine (20.9 ml, 150 mmoles) in methylene chloride (150 ml) was added methanesulfonyl chloride (8.54 ml, 110 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was solidified with ethyl acetate-n-hexane to obtain 11.45 g of the desired product (88.3%, pale yellow solid).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(I)cnc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-iodopyrimidin-2-one (556 mg) and α-bromoacetophenone (533 mg) in triethylamine (0.5 ml) and ethanol (50 ml) was stirred at ambient temperature for 71/2 hours. The resulting solution was evaporated and the residue triturated with water. This product was purified by preparative thin-layer chromatography on silica before crystallisation from ethyl acetate to give the title pyrimidinone: yield 253 mg: m.p. 155°-157°: λmaxEtOH 238.5 nm (ε 23070), 340 nm (ε 2400), λinf 250 nm (ε 17160), 275 nm (ε 1780).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20](=O)[CH2:21][C:22](OC)=[O:23])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]2[CH:21]=[C:22]([OH:23])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COC(=O)CC(=O)Cc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3cc(Cl)cc(Cl)c3)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(3,5-dichlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
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]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[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]([CH:20]([N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)[CH3:21])=[CH:16][CH:15]=3)=[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: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: O=C(O)C1CCNC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC(C(=O)O)C4)cc3)cc12

Procedure:
1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidine-3-carboxylic acid was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and pyrrolidine-3-carboxylic acid (commercially available) following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (30%). 1H NMR (Acetone-d6) TFA Salt: δ 8.81 (s, 1H), 8.75 (s, 1H), 8.70 (s, 1H), 8.28 (d, 1H), 7.59 (d, 2H), 7.37 (m, 3H), 4.46 (m, 1H), 4.21 (m 1H), 3.45 (m, 2H), 3.32 (m, 2H), 3.21 (m, 2H), 3.17 (m, 2H), 2.27 (m, 2H), 2.07 (s, 3H) 1.77 (d, 3H). LRMS [M+H]=455.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1)(=[O:21])=[O:20].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:25]=[N:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Brc1ccc2nccc(-c3ccncc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Temperature: 25 °C

Procedure:
A mixture of (6-bromo-4-(4-pyridinyl)quinoline (250 mg, 0.88 mmol), 5-methylsulfonyl pyridine-3-boronic acid (201 mg, 1.0 mmol), tetrakistriphenylphosphine palladium(0) (104 mg, 0.09 mmol), and sat. aqueous NaHCO3 (1.75 mL), in dioxane (5 mL) was heated at 110° C. for 1 h then cooled to room temperature. The rxn was filtered through Celite and Na2SO4 onto silica and the crude product was purified by column chromatography (5% EtOAc/Hex-10% Ethanol/EtOAc; 30 min gradient). Evaporation and precipitation from MeOH/water (2/98) provided the title compound as a yellow solid. (160 mg, 50%). ESMS [M+H]+=362.1