Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Br)(=[O:11])[CH3:10]>O>[C:9]([N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])(=[O:11])[CH3:10]
Reactant: Oc1cccnc1O
Reactant: CC(=O)Br
Solvent: O
Product: CC(=O)n1cccc(O)c1=O

Procedure:
2,3-Dihydroxypyridine (5.55 g) is refluxed with acetylbromide (10 ml) overnight. The reaction mixture is allowed to cool and water (10 ml) is added. The resulting suspension is extracted with methylene chloride and the methylene chloride solution is dried over Na2SO4 and evaporated. The resultant residue is recrystallised from petroleum ether (80°-100° C.) to give 1-acetyl-3-hydroxypyrid-2-one as white crystals (2.8 g), m.p. 140°-141° C.; νmax (nujol) 1680, 3120 cm-1 ; δ(d6DMSO), 2.2 (s, 3H), 6.1 (t, 1H), 6.65 (m, 1H), 7.2 (d, 1H)
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[CH2:19][N:18]([CH3:24])[CH2:17][CH:16]2[C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([CH:35]=1)[C:30](OCC)=[O:31]>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[CH2:19][N:18]([CH3:24])[CH2:17][CH:16]2[C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([CH:35]=1)[C:30]([NH:10][C:9]([NH2:11])=[NH:8])=[O:31]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)ccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(O)c(C(=O)NC(=N)N)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
2.52 g of potassium tert-butoxide was added to a solution of 2.39 g (25 mmol) of guanidine hydrochloride in 15 ml of abs. DMF and stirred at room temperature for 45 min. A solution of 950 mg (2.5 mmol) of ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate (example 29, intermediate 3) in 10 ml of abs. DMF was added, and the mixture was stirred at room temperature for four hours. After no further increase in conversion was detectable, the precipitate was removed by filtration with suction and the solvent was removed in vacuo. The residue was taken up in 2 N HCl and extracted twice with dichloromethane. The aqueous phase was adjusted to a pH of about 10 with KOH, whereupon the desired acylguanidine separates out as a colorless precipitate. Filtration with suction and drying affords 793 mg of the title compound.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22](=[O:27])C(Cl)(Cl)Cl)=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:3][CH:2]=1.CS(C)=O.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(#N)C>[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:27])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2)C(Cl)(Cl)Cl
Reactant: NCc1cccnc1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2
Yield: 12 %

Procedure:
To a solution of 10-(1,1′-biphenyl-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (0.93 g, 2.65 mmol) and N,N-dimethylaniline (0.51 mL, 3.98 mmol) in dry dichloromethane (30 mL) at 0° C. under nitrogen was added dropwise trichloroacetyl chloride (0.33 mL, 2.92 mmol). The ice bath was removed and the reaction mixture stirred at room temperature for 19 hours. The reaction mixture was then quenched by the addition of 2 M sodium hydroxide (30 mL) then partitioned between additional dichloromethane (75 mL) and 2 M sodium hydroxide (75 mL). The separated organic phase was washed with 2 M sodium hydroxide (75 mL) and water (75 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow syrup (2.12 g). Purification by flash chromatography using a solvent gradient of 1-5% ethyl acetate in hexane afforded 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.88 g, 67%) as a cream foam. To a solution of 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.4 g, 0.807 mmol) and dimethyl sulfoxide (0.29 mL, 4.034 mmol) in dry acetonitrile (5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.17 mL, 1.613 mmol) and the reaction mixture was heated to reflux for 2 days. The cooled mixture was concentrated in vacuo, the semi-solid residue dissolved in ethyl acetate (50 mL), filtered and concentrated in vacuo to afford a dark brown syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 3% methanol in dichloromethane afforded an orange semi-solid that was crystallized from dichloromethane/hexane to give the title compound (0.047 g, 12%) as a cream solid, m.p. 161-165° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1ccc(C=CC(=O)O)cn1
Reaction time: 3 h
Yield: 59.4 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g), malonic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100° for 3 hours and was allowed to cool. The mixture was evaporated to dryness, water was added to the residue and the solid was filtered off and recrystallised from ethanol-acetic acid to give 3-(6-methyl-3-pyridyl)acrylic acid (41.25 g) m.p. 213.5°-215.5°.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[C:10]([CH2:23]O)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21].CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:10]([CH2:23][C:1]#[N:3])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21]
Reactant: CCN(CC)CC
Reactant: CN(C)Cc1cccc2cc(Cl)c(CO)cc12
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
Triethylamine (0.12 ml, 0.87 mmol, 2.0 equiv) was added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-methanol (109 mg, 0.44 mmol) in CH2Cl2 (1.5 ml). At −25° C., a solution of methanesulfonyl chloride (0.05 ml, 0.66 mmol, 1.5 equiv) in CH2Cl2 (1.5 ml) was then added dropwise. After 15 minutes at 0° C., cold water (4° C., 10 ml) was added, and the mixture was extracted with CH2Cl2 (2×40 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mesylate was dissolved in N,N-dimethylformamide (2 ml) and treated at 0° C. with potassium cyanide (39 mg, 0.60 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 hours, until TLC analysis indicated complete conversion. After dilution with water (50 ml), the mixture was extracted with CH2Cl2 (2×200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 100:0 to 80:20) afforded the title compound (54 mg, 48%, mixture of 2 regioisomers). The regioisomers could be separated by preparative HPLC. Data for (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile: 1H NMR (400 MHz, CDCl3): δ=8.20 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H), 7.55 (dd, J=8.4/6.6 Hz, 1H), 4.59 (s, 2H), 3.96 (s, 2H), 2.78 (s, 6H). MS (ES+): 259 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1cccs1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in example 7. MS(m/e): 429(M+)
Reaction SMILES: CS[C:3]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:16]1)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:33][NH:34][CH3:35].ClCCl>CO>[CH3:33][N:34]([CH3:35])[C:3]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:16]1)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: CNC
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Solvent: CO
Solvent: ClCCl
Product: CN(C)C(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
Part B: To a stirred mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (4.20 gram, 8.30 mmol) in methanol (75 ml) was added dimethylamine (10 ml) and dichloromethane (75 ml) and the resulting solution was stirred at room temperature for 6 hours. Evaporation in vacuo and subsequent flash chromatographic purification (diethyl ether/petroleum ether=1/1 (v/v), followed by diethyl ether) gave a solid which was further purified by recrystallisation from diisopropyl ether to yield N1,N1-dimethyl-N2-((4-chloro-phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (2.63 gram, 63% yield). Melting point: 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][CH:35]=[CH:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: c1cc[nH]c1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccc2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 31 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), pyrrole (0.42 g) and dimethylformamide (25 ml), the title compound (0.60 g) was obtained as an amorphous solid, MS, m/z: 388.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N(CCN2CCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester and 1-(2-chloro-ethyl)-pyrrolidine gave the title compound as light yellow solid. MS: 312.0 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:21]([OH:23])=O)[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:21]([NH2:26])=[O:23])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1c(C(=O)O)n(-c2ccccc2)c2ccc(OC)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1c(C(N)=O)n(-c2ccccc2)c2ccc(OC)cc12
Yield: 75.5 %

Procedure:
A mixture of 3-ethoxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid (0.11 g, 0.35 mmol; Unangst PC, et al., J. Med. Chem. 1989;32:1360) and 1,1'-carbonyldiimidazole (0.065 g, 0.40 mmol) in 5.0 mL of tetrahydrofuran is stirred at reflux for 90 minutes. The mixture is cooled slightly and 5.0 mL of concentrated ammonium hydroxide is added. After stirring for an additional 90 minutes, the mixture is partitioned between ethyl acetate and brine. The organic layer is washed several times with fresh brine, dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from ethyl acetate-hexane yields 0.082 g (75%) of product; mp 143°-144° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][Mg]Br.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([OH:27])([CH3:32])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (0.100 g, 0.218 mmol; Example 149, Step B) in THF (4 mL) was added a solution of methylmagnesium bromide, 1.4M in toluene (0.104 g, 0.873 mmol) at 0° C. The reaction was allowed to warm to room temperature. After being stirred at room temperature for 4 h, another 1 eq. of MeMgBr was added and stirred for another 2 h. The reaction was quenched w/sat NH4Cl solution, and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography on silica gel, eluting with 40% EtOAc/hexanes, to provide the title compound as a light-yellow oil.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1)[CH:2]=C.I([O-])(=O)(=O)=[O:39].[Na+]>[Os](=O)(=O)(=O)=O.O1CCCC1.O>[OH:39][CH2:2][CH2:1][O:4][CH:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:15][CH:16]=2)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:6]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Temperature: 25 °C

Procedure:
8.54 g of tert-butyl 3-allyloxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are initially charged in a 3:1 tetrahydrofuran/water mixture (52 ml) with stirring at room temperature and admixed with 2.07 ml of osmium tetroxide (2.5% by wt. in tert-BuOH). Subsequently, 9.00 g of sodium periodate are added in portions. The reaction mixture is stirred further over 2 hours. The reaction mixture is concentrated by evaporation. The residue is suspended in a 1:1 dichloromethane/methanol mixture (150 ml), cooled to 5° C. and admixed with 3.96 g of sodium borohydride in portions. The reaction mixture is stirred at 5° C. for 1.5 hours and subsequently concentrated by evaporation. The residue is stirred in 200 ml of dichloromethane, filtered through glass fibre filter and washed with dichloromethane. The filtrate is washed with a 1:1 brine/water mixture, filtered through cotton wool, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (1:1 EtOAc-heptane). Rt=5.22.
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:14]=[N:13][C:12]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:12](=[O:23])[NH:13][CH2:14]2)=[CH:17][CH:18]=1
Reactant: O=C1N=CN(c2ccc(F)cc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 81 g 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one in 960 ml methanol and 24 ml acetic acid were added 21.2 g 10% Pd on charcoal and stirred for 16 h under a hydrogen atmosphere at ambient temperature. The reaction mixture was filtered, concentrated, diluted with 100 ml water, made alkaline with sat NaHCO3 solution and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The residue, 23 g crude product, was crystallised from AcOEt: 6.6 g 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one as colorless crystals: MS (ISP): 250.2 MH+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)C=O)C>[Cl:8][C:7]1[C:2]([N:13]2[CH:14]=[CH:15][C:11]([C:10]([F:17])([F:16])[F:9])=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 117.5 °C
Yield: 75.1 %

Procedure:
To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-trifluoromethyl pyrazole (83 g, 0.61 mol) in dry N,N-diethylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours. The reaction was cooled to 100° C. and filtered through Celite® diatomaceous filter aid to remove solids. N,N-Dimethylformamide and excess dichloropyridine were removed by distillation at atomospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141° C., 7 mm) afforded the title compound as a clear yellow oil (113.4 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:25]=[N:24][N:23]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccccc1-c1cn[nH]c1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)n1cc(-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (2.3 g, 11.5 mmol) and 4-(2-chlorophenyl)-1H-pyrazole (2.0 g, 11.0 mmol) are dissolved in 30 mL CH2Cl2 and cooled to 0° C. TEA (1.7 mL, 12.0 mmol) is added, and the reaction is allowed to warm to RT. After 30 min, additional 4-nitrophenyl chloroformate (0.25 g) and TEA are added. After 1 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to give a solid. The solid is triturated with hexanes, filtered and dried to provide 1.7 g (45%) of the crude 4-nitrophenyl 4-(2-chlorophenyl)-1H-pyrazole-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26](O)=[O:27])[C:20](=[O:29])[CH:19]=[CH:18]2)#[N:14]>>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][N:21]2[C:22]3[C:17](=[CH:16][C:15]([C:13]#[N:14])=[CH:24][CH:23]=3)[CH:18]=[CH:19][C:20]2=[O:29])[S:5][CH:6]=1
Reactant: N#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1
Reactant: Nc1scc(Br)c1-c1nc[nH]n1
Product: N#Cc1ccc2c(ccc(=O)n2CC(=O)Nc2scc(Br)c2-c2nc[nH]n2)c1

Procedure:
The title compound was prepared from 4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (253 mg, 1.03 mmol) and 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (325 mg, 1.42 mmol) according to protocol A. HPLC purification gave N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.00 min by HPLC (M+=455 and 457). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (broad s, 1H), 8.37 (s, 1H), 8.13 (d, J=9.9 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.27 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].C([N:25]1[C:29]2=NC=[C:32](C(OCC)=O)[C:33](NN)=[C:28]2C=N1)C.C(N1N2C3C4C=NNC=4N=CC=3C(=O)N(C3C=CC=CC=3)C2=CC1C)C1OC=CC=1.C(N1C2N=CC3C(=O)NC4N(N=C(C)C=4)C=3C=2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:25][C:29]4[N:1]([N:2]=[C:33]([CH3:32])[CH:28]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Agent: CC1C=C2N(c3ccccc3)C(=O)c3cnc4[nH]ncc4c3N2N1Cc1ccco1
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Product: Cc1cc2[nH]c(=O)c3cnc4c(cnn4Cc4ccco4)c3n2n1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1(a) and proceeding as in parts (a) and (b), 8-furfuryl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1, part (c), substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1-furfuryl-2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH2:44][CH3:45])=[CH:42][N:41]=[C:40]([CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH2:44][CH3:45])=[CH:42][N:41]=[C:40]([CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3CC)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (310 mg, 71%).