Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]2[N:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1.[Br:25]N1C(=O)CCC1=O>C1C=CC=CC=1.COC(C)(C)CC(C)C#N>[Br:25][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]2[N:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Agent: COC(C)(C)CC(C)C#N
Solvent: c1ccccc1
Product: O=c1c(CBr)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 23.5 %

Procedure:
The mixture of 2-methyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[ 2,3-b]pyrazine (17 g), N-bromosuccinimide (10.6 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile (167 mg) in benzene (200 ml) was refluxed for 2 hours. The mixture was washed with water and evaporated. The crude products was purified by column chromatography to obtain 2-bromomethyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (5 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28](CC2C=CC=CC=2)[CH2:27][CH2:26]1)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1)=[O:5])[CH3:2].ClC(OCC(Cl)(Cl)Cl)=O.[OH-].[K+].C(O)C>C1(C)C=CC=CC=1>[C:15]1([CH3:6])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH2:1]([NH:3][CH2:4][CH3:6])[CH3:2].[CH2:1]([N:3]([CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CCCC1CCN(Cc2ccccc2)CC1)C(=O)c1cc(-c2ccccc2)nc2ccccc12
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CCCC1CCNCC1)C(=O)c1cc(-c2ccccc2)nc2ccccc12
Product: CCNCC
Yield: 174.9 %

Procedure:
Debenzylation is carried out as in Example 48, using N-ethyl-N-[3-(1-benzylpiperidin-4-yl)-propyl]-2-phenylquinoline-4-carboxamide (21 g) in toluene (400 ml), 2,2,2-trichloroethyl chloroformate (9 g), and then a 6N aqueous solution of potassium hydroxide (245 ml) and ethanol (550 ml), as the starting materials. After chromatography of the residue on silica gel using a toluene/diethylamine mixture (9/1) as the eluant, N-ethyl-N-[3-(piperidin-4-yl)-propyl]-2-phenylquinoline-4-carboxamide (10 g) is isolated; this is converted to its methanesulphonate in ethanol by the addition of an ethanolic solution of methanesulphonic acid. The methanesulphonate melts at 164° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)\[CH2:24][CH2:25][C:26]([O:28]C)=[O:27].CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)\[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COC(=O)CC/C(=N\OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CO/N=C(\CCC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (500 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (395 mg, yield 82%) as colorless crystals. m.p. 108-109° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:7][CH:6]=1.C([Li])CCC.[C:37](Cl)(=[O:41])[O:38][CH2:39][CH3:40].[Cl-].[Na+]>O1CCCC1.CCCCCC>[CH2:39]([O:38][C:37]([N:15]([CH2:14][CH2:13][CH:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:41])[CH3:40]
Reactant: COCOc1ccc(CC(CCNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N(CCC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In argon atmosphere, 329 mg of N-[4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzene sulfonamide was dissolved in 12 ml of dry tetrahydrofuran, and cooled to 0° C., followed by addition of 0.67 ml of the solution of 1.55M n-butyl lithium in hexane, which was then stirred for 30 minutes. At the same temperature, 116 mg of ethyl chlorocarbonate dissolved in 3 ml of dry tetrahydrofuran was added dropwise and stirred at room temperature for 24 hours. To the reaction mixture was added saturated aqueous sodium chloride, and the organic phase was separated which was then extracted with ethyl acetate. The organic phases combined were washed in saturated aqueous sodium chloride and dried over magnesium sulfate, so the solvent was distilled off under reduced pressure. The obtained residue was subjected to preparative silica gel TLC which was then developed with methanol-methylene chloride (4:96 v/v) to obtain 204 mg of N-ethoxycarbonyl-N-[4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzene sulfonamide from a band of 0.36 to 0.53.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]4[C:30]5[CH:31]=[CH:32][C:33](Br)=[CH:34][C:29]=5[O:28][C:27]=4[CH:36]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50]2[NH:54][C:53]3[CH:55]=[C:56](B4OC(C)(C)C(C)(C)O4)[CH:57]=[CH:58][C:52]=3[N:51]=2)[CH:48]2[CH2:68][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50]2[NH:54][C:53]3[CH:55]=[C:56]([C:33]4[CH:32]=[CH:31][C:30]5[C:26]6[CH:25]=[CH:24][C:23]([C:20]7[NH:19][C:18]([CH:17]8[CH2:16][C:13]9([CH2:14][CH2:15]9)[CH2:12][N:11]8[C:9]([O:8][CH2:1][C:2]8[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=8)=[O:10])=[N:22][CH:21]=7)=[CH:36][C:27]=6[O:28][C:29]=5[CH:34]=4)[CH:57]=[CH:58][C:52]=3[N:51]=2)[CH:48]2[CH2:68][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:39])([CH3:38])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)oc2cc(Br)ccc23)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc4c(c3)oc3cc(-c5cnc(C6CC7(CC7)CN6C(=O)OCc6ccccc6)[nH]5)ccc34)cc2[nH]1
Yield: 87.6 %

Procedure:
To the solution of 6-[5-(7-bromo-dibenzofuran-3-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (150 mg, 0.28 mmol) and 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (78 mg, 0.56 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 90 C for 16 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-(6-{7-[2-(5-benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-dibenzofuran-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (190 mg). m/z: 775.2 (M+1), 773.3 (M−1), 338.2 (M+2)/2.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(O)(=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)cc1F
Yield: 92.4 %

Procedure:
A mixture of 29.1 g of 4-chloro-2-fluoroaniline, 29.6 g of phthalic anhydride, and 150 ml of acetic acid was heated under reflux for 2 hours under stirring. After allowing the mixture to cool, the reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to afford 50.9 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[NH:42][CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]=2[CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]3[CH:44]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1)C2
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (568 mg, 2.1 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (256 mg, 2.1 mmol), DIEA (1.1 ml, 6.3 mmol) then WSCD (520 mg, 2.7 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (450 mg, 1.9 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (503 mg, 54%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1Br.[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[CH:14].O.Cl>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[C:14][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)C#Cc1ccc(F)c(F)c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Under nitrogen replacement, 247 g of 2,3,4-trifluorobromobenzene was dissolved in 740 ml of DMF, into which 247 mL of triethylamine, 3.7 g of tetrakistriphenylphosphine palladium (0), and 4.4 g of copper iodide (I) were added, and heated to 70° C. To this, 108 g of 3-methyl-1-butyne-3-ol was added dropwise for 1 hour, and the mixutre was then stirred for 2 hours at room temperature, for 1 hour at 50° C., for 30 minutes at 60° C., and for 2 hours at 80° C. Then, 500 mL of water was added and cooled to room temperature, to which 200 mL of concentrated hydrochloric acid was added. After this was extracted twice using ethyl acetate, the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate. After the solvent was evaporated under a reduced pressure, the residue was purified by distillation under a reduced pressure (78 to 84° C./0.65 to 0.70 mmHg) to obtain 229 g of 1-(3-methyl-3-hydroxy-1-butynyl)-2,3,4-trifluorobenzene as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[C:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])#[N:28].C(OCC)C.Cl>C(OCC)(=O)C.C(OCC)C>[ClH:25].[C:27]([C:29]1[CH:30]=[C:31]([NH:32][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:33]=[CH:34][CH:35]=1)#[N:28]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2c(Nc3cccc(C#N)c3)ncc(C(=O)N3CCCCC3)c12
Yield: 26.5 %

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-cyanoaniline (56 mg) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether and then suspended in ethyl acetate (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The mixture was evaporated and dried at 40° C. under vacuum to afford the title compound (25 mg).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11]/[CH:12]=[CH:13]/[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:24])[CH2:22][CH3:23])C2)C1)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.C(O)(=O)CC(O)=O>CO>[C:1]([NH:5][CH2:10][CH2:9][CH2:8][NH:7][CH2:11]/[CH:12]=[CH:13]/[CH2:14][NH:15][CH2:20][CH2:19][CH2:18][NH:17][C:21](=[O:24])[CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1CCCN(C/C=C/CN2CCCN(C(=O)CC)C2)C1
Agent: O=C(O)CC(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: CCC(=O)NCCCNC/C=C/CNCCCNC(=O)CC

Procedure:
A mixture of 1.84 g (0.005468mmol) of (E)-1,4-bis(3-propionylhexahydro-pyrimidin-1-yl)but-2-ene (Example 17b), 44 ml of methanol, 2.74 ml (0.03405 mol) of pyridine and 4.11 g (0.03949 mol) of malonic acid is heated for 2 h under reflux and is then concentrated by evaporation in vacuo. 10 ml of 30% sodium hydroxide solution are added to the oily residue, the mixture is extracted thoroughly with ethyl acetate, the combined ethyl acetate extracts are dried over anhydrous sodium sulfate, and the resulting product is concentrated by evaporation in vacuo to a volume of about 25 ml. The crystalline precipitate that forms is filtered off and, for purification purposes, is recrystallised from acetonitrile. The resulting title compound melts at 82°-84° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][CH:22]=[C:16]2[N:15]=1.[N+:23]([O-])([OH:25])=[O:24]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:16]2[N:15]=1
Reactant: Fc1ccc(F)c([C@H]2CCCN2c2ccn3nccc3n2)c1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (3.3 g, 10.99 mmol), was dissolved in 25 mL TFA at ambient temperature to give a clear yellowish solution, then nitric acid (3.434 mL, 54.94 mmol) was added drop-wise to the solution with rapid stirring. After addition, the reaction mixture was stirred for another 15 minutes at ambient temperature, then quenched by pouring onto ice with rapid stirring. The resulting yellowish suspension was filtered, rinsed with water, then the solid was triturated with MeOH (50 mL, with brief sonication), and vacuum-filtered, giving the pure product as a fine off-white powder (2.2 g, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[C:3]([NH:8][C:9]([C@@H:11]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])[CH:4]=[N:5]1
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate and triethylamine (1.01 g) in chloroform (50 ml) was added triphenylmethyl chloride (2.78 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 1-benzyl 4-tert-butyl ((1S)-1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}tetramethylene)biscarbamate (720 mg) as an oil.
Reaction SMILES: ClC(Cl)=C[N:4]=[N:5][S:6]([C:9]1[CH:14]=CC(C)=CC=1)(=O)=O.[S-2:17].[Na+].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O>[CH2:20]([S:17][C:9]1[S:6][N:5]=[N:4][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N=NC=C(Cl)Cl)cc1
Reactant: ClCc1ccccc1
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2cnns2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ethanol (0.5 ml) solution of 1,1-dichloro-2-(p-toluenesulfonylazo)ethene (280 mg, 1.00 mmol) was slowly added to a water (1.0 ml)-ethanol (0.5 ml) solution of 600 mg (2.50 mmol) of sodium sulfide (Na2S.9H2O) under ice cooling. After 1 hr stirring at room temperature, the reaction mixture was cooled with ice. Benzyl chloride (0.5 ml) was added to the mixture and the whole was stirred for 1 hr. The reaction mixture was extracted with ether. The ethereal layer was washed with sat. aq. sodium hydrogen carbonate and sat. aq. sodium chloride, and then dried over sodium sulfate. After removal of the solvent by distillation, the residual oil was heated at 60° C. under vacuum to remove benzyl chloride and 94 mg of 5-benzylthio-1,2,3-thiadiazole was obtained as orange crystals (yield 45%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:34]5[CH2:35][CH2:36][N:31]([C:28](=[O:30])[CH3:29])[CH2:32][CH2:33]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CC(=O)N1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
30 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 was coupled to 1-acetylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 16.8 mg of 267. MS (Q1) 491.8 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[ClH:1].[C:22]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:2]([Cl:1])[CH:3]=2)=[N:8][CH2:9][CH2:10]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(C=CC2=NCCNc3ccccc32)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Product: Cl
Temperature: 80 °C

Procedure:
50 mg (0.158 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-benzo-1,4-diazepine were dissolved in a mixture of 0.1 ml of acetic anhydride and 1 ml of pyridine by heating to 80° C. The mixture was left to cool for 30 minutes then evaporated to dryness and the residue dissolved in water and ethyl acetate. The organic phase was dried over magnesium sulphate, filtered, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate for the elution. The product was dissolved in a solution of hydrogen chloride in ethyl acetate, evaporated to dryness and the residue dissolved in a small volume of acetone and left to crystallize. There was obtained 12 mg of (E)-1-acetyl-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride as an off-white solid. MS: m/e 358.9 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:28]([O:32][C:33]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.C[CH2:52][O:53]C(C)=O>>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([CH2:13][CH:2]([NH:1][C:52]([NH:41][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:34])=[CH:43][CH:42]=2)=[O:53])[C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:4])[CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(C)=O
Reactant: NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NC(Cc2cccc(OCc3ccccc3)c2)C(=O)OCc2ccccc2)cc1
Temperature: -10 °C
Yield: 68 %

Procedure:
173 (470 mg, 1.3 mmol) was dissolved in AcOEt (30 mL) and trisphosgene (0.33 equivalent, 128 mg) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 1 h. 4-(tert-butoxycarbonylamino)benzylamine (289 mg, 1 equivalent) and triethylamine (2 equivalent) were added successively and the resulting solution was stirring at room temperature overnight. 100 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 5/5) to afford 174 as white solid (540 mg, 68%). 1H NMR (DMSO): δ 1.61 (s, 9H), 3.02 (m, 2H), 4.24 (s, 2H), 4.60 (m, 1H), 5.22 (s, 4H), 6.38 (d, 1H, J=7.6 Hz), 6.62 (m, 1H), 6.70 (d, 1H, J=8.0 Hz), 6.75 (m, 2H), 7.21 (m, 4H), 7.47 (m, 11H), 9.35 (s, 1H).