Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.Cl[S:27]([C:30]1[CH:42]=[CH:41][C:33]2[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:32]=2[CH:31]=1)(=[O:29])=[O:28]>C(Cl)Cl>[CH:31]1[C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][C:33]=2[CH:41]=[CH:42][C:30]=1[S:27]([NH:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (II-1) (251 mg, 1.00 mmol) was dissolved in methylene chloride (8 ml) and triethylamine (0.238 ml, 2.00 mmol) was added thereto under a nitrogen atmosphere. To the mixture was added 2-chlorosulfonyldibenzofuran (350 mg, 1.31 mmol) under ice-cooling, and the mixture was stirred for 30 min and allowed to warm up to room temperature. The reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:4)) and recrystallized from n-hexane (10 ml) to yield methyl (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (342 mg, 0.710 mmol). Yield 71%, mp 115-116° C.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:19]=[CH:18][N:17]([CH2:20][C@@H:21]([NH:23][C:24]([C:26]3[N:27]=[C:28]([C:31](OCC)=[O:32])[S:29][CH:30]=3)=[O:25])[CH3:22])[N:16]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14]>O>[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:19]=[CH:18][N:17]([CH2:20][C@@H:21]([NH:23][C:24]([C:26]3[N:27]=[C:28]([CH2:31][OH:32])[S:29][CH:30]=3)=[O:25])[CH3:22])[N:16]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Sodium borohydride (86 mg, 2.262 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-ethyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate (502 mg, 1.131 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., water was added dropwise, the pH was adjusted to 7 and the mixture was evaporated. DCM and a few drops of methanol were added and the crude product was washed with 1M Na2CO3 and with water. Yield 58.6%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 4.31 (dd, 1H), 4.40 (dd, 1H), 4.43-4.51 (m, 1H), 4.79 (d, 2H), 6.20 (t, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.96 (dd, 1H), 7.98 (dd, 1H), 8.08 (dd, 1H), 8.13 (s, 1H), 8.50 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>C(OCCO)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:10]=1
Reactant: CCCCCCBr
Reactant: COc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCO
Product: CCCCCCOc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(OC)cc3)n2)c(O)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
15.2 g (0.038 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis(4-methoxyphenyl)-1,3,5-triazine of the formula (108b), 5.2 g of potassium carbonate and 50 mg of potassium iodide are heated in 100 ml of 2-ethoxyethanol at 110° C. for 45 minutes, followed by dropwise addition of 6.9 g (0.042 mol) of 1-bromohexane over a period of 15 minutes. The mixture is stirred at 110° C. for 12 hours, cooled to 0° C. and filtered. The solid material is washed neutral with water and then washed with methanol and dried. After recrystallization from 2-ethoxyethanol, the pure light yellow product of the formula ##STR23## is obtained.
Reaction SMILES: Br.[CH3:2][NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=O)[CH2:8]Br.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15]>C(O)C>[NH:17]([C:18]1[S:19][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([NH:3][CH3:2])[CH:5]=2)[N:20]=1)[C:14]([NH2:16])=[NH:15]
Reactant: CNc1cccc(C(=O)CBr)c1
Reactant: N=C(N)NC(N)=S
Agent: Br
Solvent: CCO
Product: CNc1cccc(-c2csc(NC(=N)N)n2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 20 gm of 3-methylamino phenacyl bromide hydrobromide, 7.65 gm of amidinothiourea and 100 ml of ethanol was refluxed for 4 hours, and then cooled to room temperature. The dihydrobromide which separated out was filtered off, dissolved in water, and the solution was made alkaline with 10% sodium hydroxide. The free base was collected and dried, yielding 11.5 gm of the title compound, m.p. 198°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:45][C:46]1([O:49][CH2:48]1)[CH3:47]>CN(C=O)C.CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:45][C:46]([OH:49])([CH3:48])[CH3:47])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
To a mixture of N-(3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxamide (5.00 g, 9.73 mmol) and Cs2CO3 (1.35 g, 4.14 mmol) in DMF/t-BuOH (15.60 mL/3.90 mL) was added isobutylene oxide (8.60 mL, 97.30 mmol). The reaction was warmed to 50° C. and stirred for three days. The reaction mixture was concentrated in vacuo and purified by a silica gel column chromatography (1:25 (v/v)=methanol/dichloromethane) to give the title compound as a white solid (2.28 g, 40%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([N:30]1CCCCC1=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:23]([N:30]1[CH2:3][CH2:2][CH:1]([NH:6][C:7]2[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12]3)[CH2:5][CH2:4]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: Cc1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
7-Amino-5-methyl-2-phenyl-1H-indole prepared in Example 2 and 1-BOC-piperidinone were reacted according to the same procedure as Preparation 23 to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34]1>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:33]2[CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:34]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.478 g, 1.76 mmol) in CH2Cl2 was added triethylamine (0.98 mL, 0.712 g, 7.04 mmol), and the mixture was cooled to 0° C. To the reaction mixture was added tert-butyl ((R)-piperidin-3-yl)methylcarbamate oxalate (prepared analogously to 2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol, oxalate salt, see Example 130; 700 mg, 2.3 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was quenched with water, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-2% EtOAc in CH2Cl2 gave tert-butyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (700 mg, 88%). LC/MS: nm/z 449.5 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[O:34].[Cl-].[NH4+]>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2([C:13]1[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1)[OH:34]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ncc(Br)c(OC)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (10 ml, 16 mmol) was added dropwise to a solution of 5-bromo-2,4-dimethoxypyrimidine (3.29 g, 15 mmol) in THF (50 ml) at −78° C. After stirring at −78° C. for 0.5 h, a suspension of 5-chloroisatin (1.27 g, 7.0 mmol) in THF (50 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 50% ethyl acetate in dichloromethane) resulted in 0.97 g of the intermediate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[CH3:13][C:3]1[C:2]2[NH:1][N:14]=[N:12][C:11]=2[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)c(N)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc2nn[nH]c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
Methyl 3,4-diamino-2-methylbenzoate (0.27 g, 1.5 mmol) was taken up in concentrated sulfuric acid (30 mL) and heated to solubilize, then cooled with an ice bath. Concurrently, sodium nitrite (0.14 g, 2.1 mmol) was solubilized in concentrated sulfuric acid (8.4 mL) using heating. This sodium nitrite solution was then cooled and added dropwise to the cooled solution of diamine. The mixture was stirred at 0° C. for 30 minutes then warmed to 60° C. for 15 minutes. The solution was then poured onto ice and extracted with 10% methanol in ethyl acetate (2×100 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 0.3 g of crude methyl 7-methyl-1H-benzotriazole-6-carboxylate, which was taken up in methanol (5 mL) and tetrahydrofuran (10 mL) and treated with 2M aqueous lithium hydroxide (5 mL), then heated to 70° C. for one hour. This solution was made acidic using concentrated aqueous hydrochloric acid, then extracted with 10% methanol in ethyl acetate (2×50 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 0.26 g of 7-methyl-1H-benzotriazole-6-carboxylic acid. 1H NMR (400 MHz, d6-DMSO): 7.94 (d, 1H), 7.72 (m, 1H), 2.95 (s, 3H). MS (EI) for C8H7N3O2: 178 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Br[CH2:13][CH2:14][CH3:15].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:13][CH2:14][CH3:15])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Cl)cc1C(N)=O

Procedure:
A stirred mixture of 5-chloro-2-hydroxybenzamide (20 g), 1-bromopropane (13.4 ml), potassium iodide (2.49 g) and anhydrous potassium carbonate (24.15 g) in acetone (250 ml) was heated under reflux for 20 hours. The cooled reaction mixture was filtered and the filter cake was washed with acetone. The filtrate and washings were combined and evaporated under reduced pressure to yield a residue which was washed with water, dilute aqueous sodium hydroxide, water and with diethyl ether to yield a crude product (19.85 g). This was recrystallised from acetonitrile, partitioned between chloroform and dilute aqueous sodium hydroxide, and was recrystallised from ethanol to yield 5-chloro-2-propoxybenzamide (16.78 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[CH2:11][CH:12]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1>[Pd].[Zn].CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[CH2:11][CH2:12][N:18]2[CH2:19][CH2:20][O:21][CH:16]([CH3:15])[CH2:17]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)CC=O)cc1
Reactant: CC1CNCCO1
Agent: [Pd]
Agent: [Zn]
Solvent: CO
Product: CC1CN(CCC(C)c2ccc(C(C)C)cc2)CCO1
Yield: 82 %

Procedure:
A mixture of 190 parts of 3-p-isopropylphenyl-3-methylpropanal, 111 parts of 2-methylmorpholine, 300 parts of methanol and 20 parts of catalyst, comprising 0.5% by weight of Pd, 0.11% by weight of Zn and 0.1% by weight of Cd on Al2O3, is hydrogenated in a stirred autoclave of 1,000 parts by volume capacity, at 120° C. under a hydrogen pressure of 50 bar, until the pressure remains constant. The autoclave is then allowed to cool, the catalyst is filtered off and the filtrate is purified by distillation. 266 parts of N-(3'-(p-isopropylphenyl)-3'-methylpropyl)-2-methylmorpholine, boiling point 122° C./0.05 mm Hg are obtained. The yield is 82% of theory.
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[CH3:22][NH2:23]>C(Cl)Cl.CCO>[CH3:22][NH:23][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(C)c1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (50 mg, 122 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with MeNH2 (153 μL of a 8 M solution in EtOH, 1.22 mmol) at rt for 2 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 22-52% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (13.2 mg, 12% over two steps). MS (ESI+) for C17H18N2O2S m/z 284 (M-NHMe)+, 315 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(Cl)c2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2cc([N+](=O)[O-])cc(Cl)c2N1
Reaction time: 6 h
Yield: 60.4 %

Procedure:
To a solution of 8-chloro-3,4-dihydro-2(1H)-quinolinone (5.08 g) in acetic anhydride (50 ml) was dropwise added a solution of nitric acid (d=1.40, 2.97 g) in acetic acid (20 ml) over the period of 10 minutes with stirring under ice-cooling. The mixture was stirred for 2 hours at ambient temperature and then for 6 hours at 50° C., and was allowed to stand for 60 hours at ambient temperature. The resulting precipitates were collected, washed with acetic anhydride and ethyl acetate successively and dried to give 8-chloro-6-nitro-3,4-dihydro-2(1H)-quinolinone (3.83 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([SH:12])[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[CH3:13]I>[OH-].[K+]>[NH2:1][C:2]1[N:3]=[C:4]([S:12][CH3:13])[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CI
Reactant: Nc1nc(S)c2cccnc2n1
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(N)nc2ncccc12

Procedure:
2-Amino-4-mercaptopyrido[2,3-d]pyrimidine (1.78 gm; 10 mmol) is dissolved in aqueous potassium hydroxide solution (1.0 gm of KOH in 25 ml of H2O), and 1 ml of methyl iodide is added at ambient temperature with stirring. After 30 minutes' reaction, the precipitated substance is subjected to suction filtration, triturated with a small amount of ethanol, and dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:29][CH3:30])=O)=[CH:20][CH:19]=3)[C:10]2=[S:31])=[CH:5][C:4]=1[C:32]([F:35])([F:34])[F:33])#[N:2].[N:36]1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27](=[NH:36])[NH:29][CH3:30])=[CH:20][CH:19]=3)[C:10]2=[S:31])=[CH:5][C:4]=1[C:32]([F:34])([F:35])[F:33])#[N:2]
Reactant: CNC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Reactant: c1ccncc1
Agent: N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CNC(=N)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 4-{4-[7-(4-Cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-phenyl}-N-methyl-butyramide (88) [ND-6] (4.0 mg, 0.008 mmol) and pyridine (1.94 μL, 0.02 mmol) in dichloromethane (3 mL) at −40° C. was slowly added triflic anhydride (Tf2O, 1.75 μL, 0.01 mmol). The mixture was allowed to warm to 0° C. over 3 h. The solution was then cooled to −40° C. and ammonia was introduced by bubbling. The reaction was then warmed to room temperature and stirred overnight. Without aqueous work up, flash chromatography using 10% methanol in ethyl acetate afforded 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-an-5-yl)phenyl)-N-methylbutanimidamide (87) [ND-3] (2.9 mg, 72%) of as a colorless oil: 1H NMR (CD3CN) δ 8.10 (d, 1H, J=8.2 Hz) 8.04 (s, 1H), 7.92 (d, 1H, J=8.2 Hz) 7.49 (br s, 2H), 7.43 (d, 2H, J=8.3 Hz), 7.30 (d, 2H, J=8.3 Hz) 3.26 (d, 3H, J=5.4 Hz) 2.77 (t, 2H, J=8.0 Hz) 2.56-2.65 (m, 2H), 2.52 (t, 2H, J=7.7 Hz) 2.42-2.52 (m, 2H), 1.95-2.12 (m, 3H), 1.47-1.62 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25]1[O:27][CH2:26]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:25][CH2:26][O:27][C:7]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: C1CO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 15 g. (51.9 mmole) of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml. of dry benzene, 9 g. (67.7 mmole) of aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 8.8 g. (0.2 mole) of ethylene oxide was added dropwise. After 18 hours of stirring at room temperature, the reaction mixture was heated to 40° for 1 hour and then cooled to room temperature and treated with 5 g. (37.6 mmole) of aluminum chloride, followed by 4.4 g. (0.1 mole) of ethylene oxide. The reaction mixture was heated 4 hours at 45°-50° and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide were added and the solid removed by filtration. The filtrate was separated and the organic phase reduced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acid and the pH of the solution adjusted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with methylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave the above-titled product as colorless rods, m.p. 183°-184°.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1/[CH:18]=[N:8]/[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1Br
Reactant: NC(c1ccccc1)c1ccccc1
Product: Brc1ccccc1/C=N/C(c1ccccc1)c1ccccc1

Procedure:
This material was prepared from diphenylmethanamine and 2-bromobenzaldehyde using the methods described by G. Cainelli et al, J. Org. Chem., 1996, 51, 5134.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[F:33][C:34]([F:41])([F:40])[CH2:35][S:36](Cl)(=[O:38])=[O:37]>>[F:32][CH:3]([F:2])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:36]([CH2:35][C:34]([F:41])([F:40])[F:33])(=[O:38])=[O:37])[CH2:30][CH2:31]1)=[O:25]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)CC(F)(F)F)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2,2,2-trifluoro-ethanesulfonyl chloride. Light-yellow solid. MS (m/z): 581.3 (M+H)+.