Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=O)[CH3:6].[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].C(O)(=O)C.N1CCCCC1>O.COCCO>[C:8]([C:10]1[C:11](=[O:12])[NH:13][C:4]([CH3:3])=[CH:5][CH:6]=1)#[N:9]
Reactant: COC=CC(C)=O
Reactant: N#CCC(N)=O
Solvent: COCCO
Solvent: C1CCNCC1
Solvent: O
Product: Cc1ccc(C#N)c(=O)[nH]1
Reaction time: 3 h

Procedure:
A mixture of 150 g (1.5 m) of 4-methoxy-3-buten-2-one, 126 g (1.5 m) of α-cyanoacetamide, and catalyst (6 cc of glacial acetic acid in 15 cc of water made basic with piperidine) in 750 cc of methyl cellosolve is refluxed and stirred for 3 hours. The solution which forms is concentrated in vacuo and the residue semi-solid is boiled in an excess of isopropanol and filtered hot. The first crop is dried to afford a 94.5 g (47%) yield of 3-cyano-6-methyl-2-pyridone, m.p. 245-246 dec. A mixture of 72 g (.537 m) of this product and 600 cc of 12N hydrochloric acid is refluxed and stirred for 6 hours. The solution is allowed to stand at room temperature for 3 days and is concentrated in vacuo. The residue solid is recrystallized with ethanol to afford a 43 g (52.5%) yield of 1H, 3-carboxy-6 -methylpyridin-2-one, m.p. 226°.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:13]1[C:14](=[O:30])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[O:28][CH3:29])[CH:16]=[CH:17][CH:18]=1>O1CCOCC1>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:14]1=[O:30]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
39.3 g of sodium tert-butylate (0.41 mol) were introduced as initial charge in 300 ml of dioxane, and 65.5 g of diethyl malonate (0.41 mol) were added dropwise over the course of 15 min such that the temperature does not exceed 30° C. After 1 h, 2.70 g (8.8 mmol) of bis(2-pyridinecarboxylato)copper(II) complex and 38.0 g (0.12 mol) of 3-bromo-1-(2-methoxy-4-nitrophenyl)pyridin-2(1H)-one were added and the reaction mixture was heated at reflux for 8 h. After cooling to RT, the mixture was further stirred overnight. The reaction mixture was filtered off from the solid with suction, the residue was after-washed with dioxane and the combined organic fractions were evaporated to ca. 300 g on a rotary evaporator. The crude solution was used in the next stage without further purification.
Reaction SMILES: B1C2CCC[CH:2]1CCC2.[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:14]=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=1.CI.C(CN)O>CCCCCC.C1COCC1>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:15]1[N:14]=[C:13]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:12]=[C:11]([NH2:10])[C:16]=1[CH2:17][NH:18][CH3:2]
Reactant: B1C2CCCC1CCC2
Reactant: N#Cc1c(N)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Solvent: CI
Solvent: NCCO
Solvent: C1CCOC1
Product: CNCc1c(N)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an atmosphere of argon, 9-BBN (0.348 ml of a 0.5molar solution in hexane, 0.174 mmol) was added to a solution of 4-amino-6-(2,4-dichloro-phenyl)-2-phenyl-pyrimidine-5-carbonitrile (60 mg, 0.174 mmol) in THF (1 ml) and stirred for 2.5 h at r.t. Potassium-tert-butylate (20 mg, 0.174 mmol) was added, followed by a drop of Methyl iodide after 10 min. The mixture was stirred overnight, then ethanolamine (11 mg, 0.174 mmol) was added and the mixture was heated to 50° C. for 3 h. After cooling, the mixture was filtered, and the filtrate was evaporated. Purification of the re-dissolved (DMF, 1 ml) residue by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) gave the title compound, MS: m/e=358.9 (M+H+), (12 mg, 19%) as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]1([N:27]=[C:28]=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1cccc2ccccc12
Product: COc1ccc(NC(=O)Nc2cccc3ccccc23)cc1-c1c(Cl)cnn1C
Yield: 60 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 1-naphthyl isocyanate in a similar manner as described in Example 1.53, providing 21.1 mg (60%) of Compound 78: LCMS m/z (%)=409 (M+H37Cl, 38), 407 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.71 (s, 1H), 8.10 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.59 (t, J=4 Hz, 1H), 7.58 (s, 1H), 7.56 (t, J=2 Hz, 1H), 7.54 (dd, J1=4 Hz, J2=2 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.41 (d, J=4 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][CH:10](OC)[CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[N:15][C:14]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[N:22][C:13]1=2>O>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:14]2[N:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH:10]=[O:9])[C:13]=2[N:22]=1
Reactant: COc1ccc2ncc(=O)n(CC(OC)OC)c2n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CC=O)c2n1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3 mL) was added to 4-[2,2-bis(methyloxy)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (0.9 g, 3.4 mmol) in water (3 mL) at room temperature and stirred for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel) using a 0-10% MeOH/DCM/1% NH4OH gradient to give the product as a mixture of aldehyde and hemiacetal (0.6 g, 80%).
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:35]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]1[CH3:43])(=[O:10])[CH3:9].CO>C(Cl)Cl>[ClH:1].[NH2:35][C@H:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)[CH:16]=2)[N:11]([C:8](=[O:10])[CH3:9])[C@@H:12]([CH3:43])[CH2:13]1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 92 %

Procedure:
4M hydrochloric acid in 1,4-dioxane (10.11 ml, 40.4 mmol) was added to tert-butyl ((2S,4R)-1-acetyl-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation, see Intermediate 64) (2 g, 4.04 mmol) at room temperature, followed by MeOH (10 mL) and DCM (10 mL) and the mixture stirred at room temperature for 2 mins. The mixture was concentrated in vacuo to give 1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (1.60 g, 3.71 mmol, 92% yield).
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.CN([CH:24]=[O:25])C>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:24]=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)c(-n2cccc2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
Anhydrous DMF (0.82 mL, 10.67 mmol) and POCl3 (0.96 mL, 10.67 mmol) were combined at 0° C. in a 50 mL round bottomed flask. The suspension was warmed to ambient temperature and treated with 1-(2-fluoro-5-nitrophenyl)-1H-pyrrole (2.0 g, 9.7 mmol) as a light yellow solution in anhydrous DMF (8 mL). The resulting mixture was vigorously stirred at room temperature for 5 hours. TLC analysis of the mixture after 5 hours showed the complete conversion of the starting material to the product. The reaction mixture was transferred to a separatory funnel and partitioned (EtOAc//H2O). The organic phase was washed with H2O (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated in vacuo to give a brown residue. The residue was purified by flash chromatography (hexanes→1:1 EtOAc/hexanes) to furnish the title compound as a white solid (1.2 g, 54%).
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC(Cl)=C(Cl)C=5)=[CH:32][CH:31]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][N:15]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:13])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:21]2[O:20][C:19]3[C:24](=[CH:25][C:26]4[CH2:27][C@@H:14]([C:12]([OH:13])=[O:11])[N:15]([C@H:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:47][CH3:48])[CH2:16][C:17]=4[CH:18]=3)[N:23]([CH3:28])[C:22]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (300 mg) was dissolved in 10 mL of dry DCM and cooled to 0° C. Boron trichloride (3 mL, 1M solution in hexanes) was added and the mixture stirred at 0° C. for 3 hours. The mixture was concentrated and treated with water/saturated sodium bicarbonate until pH 7. The aqueous mixture was extracted three times with ethyl acetate-THF (9-1) and organic layer combined. The combined organic layer were dried over sodium sulfate and concentrated to provide (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (183 mg, LC/MS: m/z 474).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)(Cl)Cl>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CCCBr
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.47 g), ethyl 4-bromobutyrate (0.32 g), triton B (0.5 ml) and chloroform was stirred for 2 days under room temperature. The reaction mixture was evaporated and the residue was subjected to a column chromatography on silica gel (20 g) with chloroform as an eluent. The fractions containing the object compound were combined (20 ml) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered off. The filtrate was evaporated to give 3-[2-(3-ethoxycarbonylpropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.49 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.CCCCCC.C(OCC)(=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: COc1cc(OC)cc(OCCCCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
A mixture of 5.51 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.42 g (0.019 mole) of 1-(3-chloropropoxy)-3,5-dimethoxybenzene and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was concentrated to dryness and the residue partitioned between chloroform-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a brown oil. The oil was subjected to chromatography on a silica gel column using a gradient elution series of hexane-ethyl acetate and ethyl acetatedimethoxyethane. After combining proper fractions eluted from the column and removing solvent, the residue oil was dried in vacuo overnight at 80° C. This produced 2.61 g (28.5%) of brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:11]=[C:12]([NH:22][C:23]([C@H:25]([NH:34]C(=O)OC(C)(C)C)[CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])[CH:13]=[C:14]4[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:16]=2[C:15]=34)=[CH:4][CH:3]=1>Cl>[NH2:34][C@H:25]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:23]([NH:22][C:12]1[CH:13]=[C:14]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:16]3=[C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:9][C:10]([CH:11]=1)=[C:15]23)=[O:24]
Reactant: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@@H](CCc4ccccc4)NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)cn1
Agent: Cl
Product: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@H](N)CCc4ccccc4)cc4c3c2C=NNC4=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A suspension of tert-butyl [(1R)-1-({[2-(6-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]amino}carbonyl)-3-phenylpropyl]carbamate 267(c) in 5 mL of 4M HCl in dioxanes was stirred at room temperature for two hours. The mixture was then filtered and the solid material washed thoroughly with ethyl ether. The title compound was obtained as a yellow solid in 48% yield after purification by reverse-phase HPLC.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.[CH3:14][CH:15]([C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:20])[C:16](O)=[O:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:14][CH:15]([C:19]([NH:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])=[O:20])[C:16]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1)=[O:17]
Reactant: N[C@H]1COc2ccccc2NC1=O
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1COc2ccccc2NC1=O
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of 0.07 g (0.37 mmol) (S)-7-amino-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in 7 ml tetrahydrofurane were added 0.15 g (0.59 mmol) 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, 0.09 g (0.59 mmol) 1-hydroxybenzotriazole hydrate, 0.12 g (0.59 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride and 1.0 ml (5.9 mmol) diisopropylethylamine. After stirring at room temperature over night the solvent was removed by distillation and the residue was purified by chromatography on silicagel with ethylacetate/heptane (gradient 0–80/100–20) to yield 0.06 g (23%) 2-methyl-N-((S)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as light yellow solid, MS m/e (%): 410.3 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CBr)c1
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 45.7 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 1.23 g of product from Example 79, 1.71 g of product from Example 25, 0.321 g of washed 50% sodium hydride and 70 ml of tetrahydrofuran. The reaction is stirred at room temperature for 68 hours. The residue is purified by column chromatography (silica gel: 25% ethyl acetate/hexane) to give 1.15 g of the desired product as a colorless oil, which crystallized on standing.
Reaction SMILES: [Sn](Cl)[Cl:2].[Cl:4][C:5]1[C:6]([N+:20]([O-])=O)=[CH:7][C:8]2[C:9]3[N:10]([C:16](=[O:19])[NH:17][N:18]=3)[C:11](=[O:15])[NH:12][C:13]=2[CH:14]=1>Cl>[ClH:2].[NH2:20][C:6]1[C:5]([Cl:4])=[CH:14][C:13]2[NH:12][C:11](=[O:15])[N:10]3[C:16](=[O:19])[NH:17][N:18]=[C:9]3[C:8]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: O=c1[nH]nc2c3cc([N+](=O)[O-])c(Cl)cc3[nH]c(=O)n12
Agent: Cl
Product: Nc1cc2c(cc1Cl)[nH]c(=O)n1c(=O)[nH]nc21
Yield: 67 %

Procedure:
672 mg (2.98 mmol) of tin dichloride were dissolved in 3.4 ml of conc. hydrochloric acid at 80° C. 200 mg (0.71 mmol) of 8-chloro-9-nitro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were added portionwise thereto. After heating at reflux for 2 hrs. the precipitate was filtered off, washed with water and dried in a vacuum. 137 mg (67%) of 9-amino-8-chloro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione hydrochloride were obtained as white crystals;
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([N+:17]([O-])=O)[C:9]=2[NH:20][CH3:21])=[N:6][NH:5][C:4](=[O:22])[CH2:3]1.O.NN>C(O)C.[Ni]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([NH2:17])[C:9]=2[NH:20][CH3:21])=[N:6][NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CNc1c(C2=NNC(=O)CC2C)ccc(C(C)=O)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1c(C2=NNC(=O)CC2C)ccc(C(C)=O)c1N
Temperature: 30 °C

Procedure:
0.65 gm of 5-methyl-6-(3-nitro-4-acetyl-methylamino-phenyl)-3-oxo-4,5-dihydro-2H-pyridazine were dissolved in 30 ml of ethanol and mixed with 0.5 ml of 80% hydrazine hydrate and 0.5 gm of Raney-nickel. The reaction mixture was heated at 30° C. for 10 minutes. After filtering off of the catalyst, the filtrate was mixed with glacial acetic acid and evaporated in vacuo. The residue was directly processed further.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]1([NH:15][NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:15][N:16]=[C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccccc1
Product: O=C1CCCC(=NNc2ccccc2)C1

Procedure:
Cyclohexane-1,3-dione is reacted with phenylhydrazine to give cyclohexane-1,3-dione monophenylhydrazone which is converted by a Fischer rearrangement into 1,2,3,4-tetrahydro-4-oxo-carbazole (see Annalen, 278, 39/1894; J.C.S., 1951, 700), dehydration of which gives 4-hydroxycarbazole. Of decisive importance for the economic carrying out of this process is the discovery of a suitable method of dehydration or of a suitable dehydration catalyst.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)N.N[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: NCCCN1CCOCC1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: NS(=O)(=O)O
Product: Nc1nc2nc(NCCCN3CCOCC3)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (4.00 g) from Example 1, sulfamic acid (2.53 g) and aminopropylmorpholine (30 mL) was reacted as in Example 53. In this instance, the crude residue was washed with hot ethyl acetate followed by diethyl ether to afford 3.95 g of the title compound 6-(2,6-dichlorophenyl)-N2 -(3-morpholin-4-yl-propyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 461=M+ +C2H5, 433=M+ +H (Base), 346, 332; mp 224°-230.5° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C=C(N2CCOCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.60 g, 1.59 mmol) and morpholine (3 ml) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([Br:13])[CH:5]=1.Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([Br:13])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(Br)c1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of 3-bromo-5-nitro-benzoic acid methyl ester (D11) (12.1 g, 46.5 mmol, 1 equiv) in MeOH (200 ml) was added SnCl2 (44 g, 233 mmol, 5 equiv). The resulting mixture was stirred at reflux for 4 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ice-cold AcOEt and H2O. The aqueous phase was basified with 2N aqueous NaOH solution until a white precipitate appeared, then slowly with 12.5N aqueous NaOH solution until this precipitate disappeared. The temperature was kept below 10° C. during this addition. The two layers were separated and the aqueous phase extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 3-amino-5-bromo-benzoic acid methyl ester (D12) (9.9 g, 93%) as a brown solid.