Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:20]=2)=[C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[N:10]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([C:8]2[S:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[N:10][C:9]=2[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH:24]=[CH:23][N:22]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccnc(NC(=O)c3ccccc3)c2)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Acetyl chloride (0.26 mL, 3.7 mmol) and 4-dimethylaminopyridine (0.09 g, 0.76 mmol) were added to a solution of N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.96 g, 2.4 mmol) in N,N-dimethylacetamide (20 mL) and the mixture was stirred at 70° C. for 16 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethyl acetate to obtain 0.32 g (yield 30%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 165.4 %

Procedure:
A mixture of 3.2 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.46 g of 2-(dimethylamino)ethyl chloride hydrochloride, 3 g of potassium carbonate and 75 ml of acetone is treated in the same manner as described in Example 1. The product thus obtained is converted into its hydrochloride and recrystallized from a mixture of chloroform, ethanol and ether. 3.4 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(#N)C.CCOCC>[NH2:12][C:10]([C@@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: CC[C@H](N)C(N)=O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC[C@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 78.7 %

Procedure:
345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propy]-4-chlorobutanamide.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([NH2:34])[CH:27]=1)=[O:4].C1COCC1.CO>O>[NH2:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[C:32]#[N:33])[CH2:25][N:6]1[C:7](=[O:24])[CH2:8][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:10][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(CN2C(=O)CN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2C(=O)O)cc1N
Reaction time: 16 h
Yield: 39.6 %

Procedure:
Water (5 drops) is added to a solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (30 mg, 0.05 mmol), EXAMPLE 99, in a 1:1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (7 mg, 1.66 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 10 mg (34%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.18 (dd, J=12.1, 3.5 Hz, 1H), 3.61 (d, J=16.0 Hz, 1H), 3.77 (d, J=16.0 Hz, 1H), 3.95 (d, J=16.0 Hz, 1H), 4.06 (d, J=12.1 Hz, 1H), 4.14 (m, 1H), 6.40 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.57 (dd, J=8.6, 1.9 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.18 (s, 1H), 8.33 (s, 1H) ppm; MS (ISP loop): m/z 505 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17](OC)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[S:25][CH:26]=[C:27]([CH3:29])[N:28]=4)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Product: Cc1csc(NC(=O)C2=C(O)c3sc4cc(Cl)ccc4c3S(=O)(=O)N2C)n1
Yield: 36 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 36% of theory.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N)nc(C#Cc2ccccc2)c1-c1cncnc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-6-(2-phenylethynyl)-5-pyrimidin-5-ylpyridin-2-amine C3c (400 mg, 1.3 mmol), sodium methoxide (a solution of 2.61 mmol in 0.29 ml MeOH) and MeOH (2 ml) is stirred for 20 minutes at 100° C. and 10 minutes at 110° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over Na2SO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 228 mg (58%). HPLC-MS: M+H=303.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:6](=[N:21]OC(NCCC)=O)[C:5]1=[O:29].[ClH:30].O1CCOCC1>CO.CCOCC.[C].[Pd]>[ClH:30].[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7][CH:6]([NH2:21])[C:5]1=[O:29]
Reactant: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccccc2N(COC)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: COCN1C(=O)C(N)CN(c2ccccc2)c2ccccc21
Yield: 69.3 %

Procedure:
10% Palladium carbon (2.0 g) was added to 1-methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (14.2 g) suspended in methanol (200 ml), and the resultant mixture was stirred for two hours under hydrogen atmosphere (3 kg/cm2) at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), to thereby obtain a yellow oily substance. The substance was dissolved in ether, and 4N hydrochloric acid-dioxane (10 ml) was added thereto. Crystals so precipitated were collected by filtration, to thereby obtain 8.28 g of the title compound as a white solid (yield: 69.3%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12]1.C(N(CC)CC)C>C(OCC)C>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2([CH2:25][NH:26][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cc(C2(CN)CCCC2)c2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1cc(C2(CNC(=O)c3ccccc3)CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction is performed under a dry nitrogen atmosphere. 9.8 g (0.07 mol) of benzoyl chloride dissolved in 70 cm3 of diethyl ether are added dropwise to a solution of 16 g (0.07 mol) of 1-(1-methyl-3-indolyl)-cyclopentylmethylamine and 7.08 g (0.07 mol) of triethylamine in 70 cm3 of diethyl ether so as to maintain a gentle reflux of the ether, and the mixture is then stirred for 2 hours at room temperature. The precipitate formed is thereafter drained, the ether solution is washed with water, dried over sodium sulphate and filtered and the ether is evaporated off from the filtrate. The residue thereby obtained is crystallised by washing with cold diisopropyl ether.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[NH2:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:23][CH:24]1[C:30]2[CH:31]=[C:32]([O:37][CH3:38])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:23][CH:24]1[C:30]2[CH:31]=[C:32]([O:37][CH3:38])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[CH2:28][CH2:27][CH2:26][N:25]1[CH2:2][C:3]([NH:17][CH:12]1[C:13]2[C:9](=[C:8]([O:7][CH3:6])[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COc1cccc2c1CCC2N
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NC2CCc3c(OC)cccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-4-methoxy-indan-1-ylamine and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(N(CC)CC)C>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[C:26]([F:25])([F:36])[F:37])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1.44 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.15 g of triethylamine and 0.300 g (1.44 mmol) of 2-trifluoromethylbenzoyl chloride is stirred at room temperature for 2 hours and then washed with 1N HCl 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give a solid. Crystallization from dichloromethanehexane gives 0.41 g of crystals, m.p. 191°-193° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[C:32]([N:47]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:48](=[O:51])[O:49][CH3:50])[CH:33]=[C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:46][O:45][CH2:44]3)[CH2:39][CH2:38]2)[C:35]=1[F:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:14]([C:13]1[N:9]2[C:10]([C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:6][C:7]([NH:29][C:30]3[CH:31]=[C:32]([N:47]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=4)[C:48](=[O:51])[O:49][CH3:50])[CH:33]=[C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH:43]5[CH2:46][O:45][CH2:44]5)[CH2:41][CH2:42]4)[C:35]=3[F:36])=[N:8]2)=[N:11][CH:12]=1)#[N:15]
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C3COC3)CC2)c1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c(F)c(N2CCN(C3COC3)CC2)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 179.8 %

Procedure:
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 3) (58.4 mg, 0.146 mmol), methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (62 mg, 0.098 mmol) and Cs2CO3 (95 mg, 0.293 mmol) in DMF (1 ml) were heated at 70° C. for 80 minutes. Additional 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (58.4 mg, 0.146 mmol) and Cs2CO3 (95 mg, 0.293 mmol) were added and the mixture stirred at 45° C. for 16 hours. The mixture was partitioned between EtOAc and dilutes aq. NH4Cl solution. The organic layer was washed twice with dilute NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness to give methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4 methoxybenzyl)carbamate (134.4 mg). The material was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.CO.O.[NH2:24]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:24]
Reactant: NN
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NCC(N)=N2
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)=NCC(NN)=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 26.5 parts of 2-amino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine, 500 parts by volume of methanol and 1.2 parts of glacial acetic acid is added 25 parts of 100% hydrazine hydrate. The mixture is stirred for 1 hour at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals melting at 110° C to 120° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Yield: 73 %

Procedure:
A mixture of ethyl 4-bromobenzoate (1.5 g, 6.55 mmol), ethynyl trimethylsilane (965 mg, 9.82 mmol), diisopropylamine (1.39 g, 13.7 mmol), cuprous iodide(25 mg, 0.131 mmol), and bis(triphenylphosphine) palladium(II) chloride (184 mg, 0.262 mmol) was heated at 45° C. for 4 h in dry THF (10 ml) under argon atmosphere. The reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=100/1) to give ethyl 4-[(trimethylsilyl)ethynyl]benzoate (73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=O)=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl) amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (40 mg, 34%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[CH2:15]([O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:24]=1
Reactant: c1ccc(COc2cccnc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1cccc(OCc2ccccc2)c1

Procedure:
A solution of O-mesitylenesulfonylhydroxylamine (13.7 g, 44.6 mmole, purity of 70%) in methylene chloride (150 ml) was added dropwise to a solution of 3-benzyloxypyridine (8.25 g, 44.6 mmole) in methylene chloride (150 ml) under ice-cooling, with stirring. The reaction solution was returned to room temperature, stirred for 1 hours and concentrated to one-quarter of the original volume at 20° to 30° C., and ether was added to the concentrate, thereby white crystals were precipitated. This product was used in the next reaction, without being purified.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
2-Chlorobenzaldehyde (1z, 2.00 ml, 17.8 mmol) and acetone (19, 0.65 ml, 8.8 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 1.80 g (67%) of a yellow solid: mp 119-121° C. [expected mp 110° C.]; 1H NMR: δ 7.04 (d, 2H, J=16.1 Hz), 7.29 (m, 4H), 7.41 (m, 2H), 7.67 (m, 2H), 8.11 (d, 2H, J=16.1 Hz); 13C NMR: δ 127.0, 127.5, 127.6, 130.1, 131.1, 132.9, 135.3, 139.2, 188.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Yield: 68.5 %

Procedure:
Reaction of 3,5-dichlorobenzaldehyde (26.9 g, 0.154 mole), malonic acid (24.1 g, 0.232 mole), pyridine (8 ml) and piperidine (0.4 ml) substantially as above yielded 22.9 g (69%) of 3,5-dichlorocinnamic acid as white needles: mp 169-170° (ethanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:25]([C:21]2[CH:20]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:24]=[CH:23][N:22]=2)=[O:26])[CH2:39][CH2:38][CH2:37]1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: C1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and azetidine hydrochloride (Aldrich, Cat. No. 414336). LCMS (M+H)+: m/z=499.2.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2ccccc2)cc1F
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (270 mg, 0.449 mmol) prepared in Example 1a and triethylsilane (0.30 mL) in dichloromethane (3.0 mL), trifluoroacetic acid (3.0 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=95:5) to yield the title compound (186 mg, 92%) as a colorless solid.