Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[CH:19][C:18]=2[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].CCO>O>[F:25][CH:24]([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:28])=[C:18]([CH3:27])[CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC(F)F)cc2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(OC(F)F)ccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
The mixture of 2-(4-difluoromethoxy-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (243) (301 mg, 0.77 mmol), KOH (50% aqueous solution, 1.73 g, 15.5 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (10 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration affords 2-(4-difluoromethoxy-2-methyl-benzoylamino)-indan-2-carboxylic acid (244) as white solid (245 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:25]5[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=5)[C:19]#[N:20])[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-cyanophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 331.0 (M+H)+, retention time 1.27 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:21][CH2:20][C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:21][CH2:20][C:14]2[N:15]=[N:16][C:17]([NH:23][NH2:24])=[CH:18][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)OCc1ccccc1)C2

Procedure:
19.2 g of crude oily 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid benzyl ester and 100 cc of hydrazine hydrate are stirred at a bath temperature of 70° for 71/2 hours, and the mixture is worked up to the crude title compound in a manner analogous to that described in Example 37, and this compound is recrystallized from acetonitrile. M.P. 135°-137° (decomp.).
Reaction SMILES: O[C:2]1(C#C)CC(C)CC(C)(C)C1.[CH3:13][C:14]1([CH3:27])[CH2:19][CH:18](C)[CH2:17][C:16]([C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])=[CH:15]1>>[CH3:27][C:14]1([CH3:13])[CH:19]([CH3:2])[CH2:18][CH:17]=[C:16]([C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:15]1
Reactant: C#CC1(O)CC(C)CC(C)(C)C1
Reactant: C=CCCC(=O)C1=CC(C)(C)CC(C)C1
Product: C=CCCC(=O)C1=CCC(C)C(C)(C)C1

Procedure:
1-Hydroxy-1-ethynyl-3,3,5-trimethyl-cyclohexane used as starting material for the following preparation was prepared in accordance with W. Ziegenstein, "Aethinylierung und Alkinylierung", p. 9, Verlag Chemie (1963). The conversion into 1-(3,3,5-trimethyl-cyclohex-1-en-1-yl)-pent-4-en-1-one was performed according to the procedure described in pathway I, paragraph (d). The analytical data were as follows:
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1SC=CN=1.C(N)C>C(O)C>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)#[N:2]
Reactant: CSC(=NCCSCc1nccs1)NC#N
Reactant: NCCSCc1nccs1
Agent: CCN
Solvent: CCO
Product: CCNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea, prepared by reacting 2-[(2-aminoethyl) thiomethyl]thiazole with dimethyl-N-cyanoimidothio carbonate in ethanol by the procedure of Example 97, with ethylamine in ethanol under reflux for 8 hours gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylthio)ethyl]-guanidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].CC1(C)[O:34][C@H:33]([CH2:35][O:36][NH2:37])[CH2:32][O:31]1>>[OH:34][C@@H:33]([CH2:32][OH:31])[CH2:35][O:36][NH:37][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: CC1(C)OC[C@@H](CON)O1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@@H](O)CO)c(=O)n(C)c1=O

Procedure:
Example 37 was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with (S)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (See, Bailey et al., J. Med. Chem., 34, 1991, 51-65), followed by acid hydrolysis of the resulting material. 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2 H) 6.79 (t, J=8.0 Hz, 1 H) 3.89 (m, 3 H) 3.66 (m, 1 H) 3.55 (m, 1 H) 3.31 (s, 3 H) 3.02 (s, 3 H). [M+H] calc'd for C16H18FIN4O6, 509; found, 509.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=O)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[N:31][OH:32])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C=NO)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.6 g), hydroxylamine hydrochloride (495 mg) and sodium acetate (691 mg) in acetic acid (20 ml) was stirred at room temperature for an hour to form diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (2.18 ml) and the mixture was heated at 110° C. for 3.5 hours with stirring. Acetic acid was distilled off under reduced pressure from the reaction mixture and the resultant residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The resultant oil (2.88 g) was chromatographed on a column of silica-gel (72 g), and eluted with a mixture of benzene and ethyl acetate (10:1, v/v) to give an oil (1.6 g), which was triturated with diisopropyl ether (3 ml) to give crystalline powder (1.3 g). Recrystallization from a mixture (20 ml) of diisopropyl ether and ethanol (15:1, v/v) gave pure crystals of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.03 g), mp 126° to 127° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:18][N:19](C)C=O>CN1C(=O)N(C)CCC1>[C:18]([C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:19]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C)ccc1Cl
Reactant: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(C)Oc1cc(C)ccc1C#N
Temperature: 200 °C
Yield: 38 %

Procedure:
In a similar manner to Example 48(ii), but starting from ethyl 2-(2-chloro-5-methylphenoxy)-2-methylpropionate instead of ethyl 2-(2-bromo-4-methylphenoxy)-2-methylpropionate and using DMPU as solvent in place of dimethylformamide and heating for 18 hours at 200° C. there was obtained, after evaporation of the dichloromethane extracts a liquid. This was dissolved in ether (200 ml) and the solution washed with water (3×50 ml) to removed the DMPU, then dried (MgSO4) and evaporated. The residue was purified by MPLC, eluting with 10% v/v ethyl acetate in hexane to give ethyl 2-(2-cyano-5-methylphenoxy)-2-methylpropionate (38%) as a colourless oil; NMR (250 MHz, CDCl3): 1.24(3H,t J=7 Hz), 1.67(6H,s), 2.33(3H,s), 4.24(2H, q J=7 Hz), 6.60(1H,s), 6.84(1H,dm, J=8 Hz), 7.44(1H,d J=8 Hz); m/e 265 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[N:8]=[CH:7]2.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[F:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[CH:3]=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[N:8]=[CH:7]3)=[CH:32][CH:33]=1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(Br)c3n2)cc1
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(-c4ccc(F)nc4)c3n2)cc1

Procedure:
To a 0.050 M solution of 4-(8-bromo-6-(trifluoromethyl)quinazolin-2-ylamino)benzenesulfonamide (1.0 eq) in DME was added 2-fluoro-5-pyridineboronic acid (3.0 eq), (dppf)Pd(II)Cl2-CH2Cl2 (0.050 eq) and 2M aqueous potassium carbonate (8.0 eq). The mixture was microwaved at 120° C. for 10 min and then diluted with ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to give the desired product which was used without further purification. ES/MS m/z 464 (MH+).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][C:15]([OH:17])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 42.3 %

Procedure:
Proceeding as in Example 1, but substituting (S)-2-(2-(tert-butoxycarbonyl)pyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 103, (S)-tert-butyl 1-(2-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)pyrrolidine-2-carboxylate (3 mg, 42.3%). MS (EI) for C33H38FN3O6. found 592.7 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:16])([CH2:9][CH2:10]C(OCC)=O)[CH:3]1[CH3:17].[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:16])([CH2:9][CH2:10][NH2:18])[CH:3]1[CH3:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCC1(C)C(C)CCN(C)C1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CCN(C)C(C)C1(C)CCN
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate (34.0 g, 141 mmol) was dissolved in concentrated sulfuric acid (300 mL) under a nitrogen atmosphere and the mixture was heated to 60° C. Sodium azide (18.35 g, 282 mmole) was then added in small portions (300-500 mg) over a three hour period at such a rate that a temperature range of 50°-70° C. was maintained. The mixture was then stirred at 60° C. for 2 hours, cooled to room temperature and poured onto ice-water (800 mL). The solution was basified with 35% NaOH and extracted with ether (3X). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo to afford 18.5 g (71%) of 1,2,3,4-tetramethyl-3-piperidineethanamine as a yellow oil. The product was treated with ethereal HCl to afford the product as a dihydrochloride salt. The salt was isolated as a white powder and had a melting point of 233°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(CN=[N+]=[N-])c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CN)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 2-choro-4-cyanobenzyl azide (5.8 g, 30.1 mmol) in THF/H2O (3:1), was added triphenyl phosphine (12.3 g, 46.7 mmol). The reaction was stirred at room temperature overnight, then neutralized with 1N sodium hydroxide, extracted with ethyl acetate (150 ml×3). The organic layer was dried over sodium sulfate, and then solvent was removed in vacuo. The product was purified by silica-gel chromatography column with methanol/ammonia hydroxide/ethyl acetate (20:1:69) to give 4.5 g (90%) of 2-chloro-4-cyanobenzylamine. NMR (CDCl3): δ 4.0 (s, 2H, CH2), 7.58 (d, 2H, HAr), 7.62 (s, 1H, HAr)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.[CH:37]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:38].C(=O)([O-])[O-].[K+].[K+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:42]4[CH:43]=[CH:44][C:39]([CH:37]=[O:38])=[CH:40][CH:41]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (500 mg), 4-formylphenylboronic acid (166 mg), potassium carbonate (638 mg) and bis(triphenylphosphine)palladium(II) chloride (64.8 mg) were added to a 20 ml microwave vial. Ethanol (9 ml) and toluene (9 ml) were added to the vial. The reaction mixture was heated in a microwave at 120° C. for 20 min. The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated, and the residue was chromatographed (0-5% methanol:DCM) to give (S)-2-(6-(4-chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (327 mg) as a brown solid. LCMS (formate): MH+ 498/500, RT 0.98 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][CH2:27][OH:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][CH:27]=[O:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 3-(1-trityl-1H-imidazol-2-yl)-propan-1-ol (201 mg, 0.545 mmol) in CH2Cl2 (6 mL) was added Dess-Martin periodinane (278 mg, 0.655 mmol) at room temperature. After stirring at room temperature for 1 h, the mixture was diluted with EtOAc (30 mL), washed with 1 N NaOH(aq) (2×10 mL) and brine (10 mL), then dried (MgSO4) and concentrated in vacuo to give a tan foam (178 mg, 89%). 1H NMR (CDCl3) δ 2.19 (m, 2H), 2.37 (m, 2H), 6.75 (d, 1H, J=1.5 Hz), 6.93 (d, 1H, J=1.5 Hz), 7.13 (m, 6H), 7.34 (m, 9H), 9.54 (s, 1H).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH3:12].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[CH3:12])=[CH:14]1
Reactant: CN1C(=O)c2ccccc2C1O
Reactant: c1ccc2[nH]ccc2c1
Product: CN1C(=O)c2ccccc2C1c1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
The product from example 20, step a) (650 mg, 3.98 mmol) and indole (780 mg, 6.67 mmol) were heated (neat) to 180° C. for 30 minutes. The reaction was cooled to rt and the product was recrystallized from ethanol/water to give 452 mg of the sub-title compound as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[C:9](=[O:19])[N:10]3C(C4C=CC=CC=4)[O:12][C:3]=1[C:4]=23.[CH2:26](O)[CH3:27]>>[CH2:26]([O:19][CH:9]1[CH:8]2[CH2:20][CH2:21][CH2:22][N:7]2[C:6](=[O:23])[C:5]2[CH:24]=[CH:25][C:2]([CH3:1])=[C:3]([OH:12])[C:4]=2[NH:10]1)[CH3:27]
Reactant: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Reactant: CCO
Product: CCOC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Temperature: -20 °C
Reaction time: 72 h

Procedure:
350 mg of 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo(5,4,3-jk)pyrrolo(2,1-C)(1,4)benzodiazepin-6,11-dione was treated in the same manner as in Example 4. The concentrate of the chloroform layer obtained was dissolved in 2 ml of hot ethanol, cooled to -20° C., and allowed to stand at this temperature for 3 days. Thus, 86 mg of 2,3,5,10,11,11a-hexahydro-11-ethoxy-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained in a colorless crystalline form. Recrystallization of the resulting product from ethanol gave a colorless needle-like crystal having a melting point of 155° to 157° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:22]3[C:21](=[O:33])[NH:20][C:19](=[O:34])[N:18]([CH3:35])[C:17]=3[C:16]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:22]3[C:21](=[O:33])[N:20]([CH2:41][C:42](=[O:43])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:19](=[O:34])[N:18]([CH3:35])[C:17]=3[C:16]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)[nH]c(=O)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)n(CC(=O)c3ccccc3)c(=O)n(C)c12
Yield: 84.3 %

Procedure:
A solution of methyl 6-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (50 mg), α-bromoacetophenone (27 mg) and potassium carbonate (25 mg) in N,N-dimethylformamide was stirred at 25° C. for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (51 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:34][CH2:33][N:25]2[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=3[CH:32]=[C:24]2[C:23]1=[O:35])(=[O:3])[CH3:2].Cl[C:37]1[CH:38]=[C:39]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:62][O:61][CH2:60]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:40]2[N:41]([N:43]=[CH:44][N:45]=2)[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:22]2[CH2:34][CH2:33][N:25]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=4[CH:32]=[C:24]3[C:23]2=[O:35])=[CH:8][C:9]([F:21])=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:60][O:61][CH2:62]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:40]2[N:41]([N:43]=[CH:44][N:45]=2)[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2ncnn2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c3ncnn3c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 93.2 %

Procedure:
A mixture of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l (165 mg, 0.38 mmol), 108d (140 mg, 0.38 mmol), PdCl2(dppf) (41 mg, 0.056 mmol), K3PO4 (100 mg), and NaOAc (50 mg) in MeCN (10 mL) and H2O (3 mL) was heated at 110° C. in sealed tube for 2 h. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography to afford 108e (250 mg, 60%). MS: [M+H]+ 706.