Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5](B(O)O)=[CH:6][CH:7]=1)[CH3:2].Br[C:12]1[S:16][C:15]([S:17]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[CH2:1]([C:3]1[S:4][C:5]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)(=[O:18])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1)[CH3:2]
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: CCc1ccc(B(O)O)s1
Product: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)s1

Procedure:
N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 2-ethylthiophene-5-boronic acid (411 mg, 2.64 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 6.30 mg of the pure product as a dark brown solid (90% yield).
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[C:26]2=[O:34])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][N:9]([C:31](=[O:32])[CH2:30][N:27]3[CH2:28][CH2:29][C:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)([C:35]4[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=4)[C:26]3=[O:34])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpyrrolidine (Example 17A, 0.22 g, 1.00 mmol) in dichloromethane (25 mL) under nitrogen was added 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.33 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.39 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.36 (m, 14H), 6.95-7.01 (m, 4H), 4.22 (s, 1H), 4.17 (s, 1H), 4.10 (s, 1H), 4.08 (s, 1H), 3.51-3.60 (m, 3H), 3.42 (t, J=6.7 Hz, 1H), 2.72-2.80 (m, 2H), 2.62 (t, J=6.6 Hz, 1H), 2.53 (t, J=6.8 Hz, 1H); MS (DCI+) m/z 537 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[NH:5][C:6]=1[CH2:7][CH2:8][CH3:9].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[N:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1[nH]c(C=O)cc1Br
Product: CCCc1c(Br)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 75 %

Procedure:
This compound was prepared using the same procedure as in Example 1. 4.3 g of 4-bromo-5-n-propyl-2-pyrrolaldehyde (0.020 moles) and 11 g of 4′-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl (0.020 moles) yield 10 g of product which are used in the subsequent step. Formula: C41H34BrN5O (m.w. 692.66). Yield 75%.
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>C1COCC1.O.CO>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(N4CCCC4)c(C(F)(F)F)c3)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(N4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 2-(7-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (17.8 mg, 0.037 mmol) in 5 mL (THF/water/MeOH 3:1:1), LiOH hydrate (7.68 mg, 0.183 mmol) was added. After stirring at room temperature for 2 h, the mixture was partially concentrated and the residue was extracted with 0.5 M citric acid and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated to give the title compound as a brownish sticky solid (16.3 mg). LCMS m/z=459.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.95 (m, 4H), 2.09-2.16 (m, 1H), 2.57-2.64 (m, 1H), 2.73-2.90 (m, 4H), 3.27-3.35 (m, 4H), 3.53-3.59 (m, 1H), 4.99 (s, 2H), 6.82 (dd, J=8.8, 2.4 Hz, 1H), 6.96-7.01 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.45 (dd, J=8.6 Hz, 2.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: c1ccc2c(c1)NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1Cl)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A slurry consisting of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 88, 0.492 g), 2-chlorobenzoyl chloride (0.268 ml), dimethylaminopyridine (0.0538 g), diisopropylethylamine (0.368 g), and THF (9 ml) is stirred at 20°-25° for 1.5 hr. The mixture is then partitioned between ethyl acetate, aqueous sodium bicarbonate, and saline. The product is poorly soluble in both the organic and aqueous phases, filtration of the extraction solvents gives additional material. The crude product is then triturated with ethyl ether and dried to give the title compound, mp 254°-256°; MS (m/z) at 417, 419; IR (mineral oil) 1659, 1576, 1508, 765 and 1394; NMR (CDCl3) 8.16 δ.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Yield: 84.1 %

Procedure:
The compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (226 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (390 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25](Cl)=[CH:24][N:23]=1)COCCO[Si](C)(C)C)(=[O:11])=[O:10].[CH2:31]([OH:34])[C:32]#[CH:33].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25]([O:34][CH2:31][C:32]#[CH:33])=[CH:24][N:23]=1)(=[O:10])=[O:11]
Reactant: C#CCO
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g), propargyl alcohol (0.025 mL) and sodium hydride (0.035 g of a 60% dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.05 g.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH3:4].C([O-])(O)=O.[Na+].Cl.[NH2:12][NH:13][C:14]([NH2:16])=[O:15]>O.C1COCC1>[N:12](=[C:3]([CH3:4])[CH2:2][Cl:1])[NH:13][C:14]([NH2:16])=[O:15]
Reactant: CC(=O)CCl
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCl)=NNC(N)=O

Procedure:
Add 1.0 gm chloroacetone and a solution of 0.84 gm NaHCO3 in 10 ml water to a solution of 1.1 gm semicarbazide hydrochloride in 25 ml THF and stir overnight. Two layers form. Separate the top layer and concentrate to obtain an off-white solid, 2-semicarbazono-1-chloropropane.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:15][C:13]=2[N:14]=1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) as a TFA salt (708 mg, 2.0 mmol) in anhydrous DMF (5 ml) was added triethylamine (5550, 4.0 mmol) and the reaction was stirred at RT for two hours. After this time, ethyl chloroformate (228 μl, 2.4 mmol) was added dropwise and the reaction was stirred at RT overnight. The reaction was partitioned between water and ethyl acetate and the aqueous phase was extracted into ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulphate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C1(C=CC=C(O)C=1)O.C(O[C:41]1[CH:57]=[CH:56][C:44]([C:45]([O:47]C2C=CC(C=O)=CC=2)=[O:46])=[CH:43][CH:42]=1)CCCCCCCC=C.[O-]Cl=O.[Na+]>>[CH2:11]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:41]2[CH:57]=[CH:56][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=2)=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Reactant: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (2.11 g, 19.1 mmol), 12 (5.6 g, 14.7 mmol), NaH2PO4·H2O (6.89 g, 44.2 mmol), NaClO2 (7.72 g, 85.4 mmol). Yield 5.8 g (quant). 1H NMR: δH (CDCl3; 300 MHz): 1.27-1.57 (10 H, m, CH2), 1.85 (2 H, m, O—CH2—CH2), 2.08 (2 H, m, CH2═CH—CH2), 4.07 (2 H, t, 3J=6.6 Hz, O—CH2), 4.99 (2 H, m, CH2═CH), 5.84 (1 H, m, CH2═CH), 7.00 (2 H, d, 3J=8.9 Hz, Ar—H), 7.36 (2 H, d, 3J=8.6 Hz, Ar—H), 8.17 (2 H, d, 3J=8.9 Hz, Ar—H), 8.22 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.4, 29.5, 29.7, 29.8, 34.2, 68.7, 114.6, 114.8, 121.34, 122.4, 127.0, 132.8, 139.5, 156.0, 164.2, 164.7, 171.7.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C1COCC1.[OH-].[Na+]>[CH2:21]([O:20][C:18](=[O:19])[NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CO)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(CO)cc1F)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-3-fluorobenzylalcohol (20.7 g, 147 mmol) and pyridine (35.5 ml, 79 mmol) in THF (320 ml) and 2N NaOH (80 mL) was added benzyl chloroformate (24.8 mL, 170.6 mmol) at 0° C. over a period of 15 min. The reaction mixture was stirred for 20 min at 0° C. and for 2 h at room temperature. The reaction was quenched with water and diluted with EtOAc. The phases were separated and the organic phase was washed with 5% NaHSO4, saturated aq. NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The title compound was crystallized from EtOAc and cyclohexane: TLC (cyclohexane-EtOAc 3:1) Rf=0.45; HPLC RtE=1.02 min; ESIMS [M+NH4]+=293; ESIMS [M−H]−=274; 1H NMR (360 MHz, CDCl3): δ 8.00 (t, 1H), 7.40-7.25 (m, 5H), 7.10-7.00 (m, 2H), 6.82 (s broad, 1H), 5.15 (s, 2H), 4.55 (d, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([CH2:14][C:15](Cl)=[O:16])=[O:13])[CH3:10]>C(Cl)Cl>[CH2:1]([NH:8][C:15]([CH2:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of benzylamine (43.24 g) and methylene chloride (300 ml) is cooled with ice-water, and a solution of ethoxycarbonylacetyl chloride (29.63 g) in methylene chloride (150 ml) is added dropwise thereto. The mixture is stirred at the same temperature for 2 hours. The mixture is filtered to remove precipitates (benzylamine hydrochloride). The filtrate is washed with 2% hydrochloric acid and a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby ethyl (N-benzylcarbamoyl)acetate (42.15 g) is obtained as colorless needles. Yield: 96.8%.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]([NH2:15])[C:6]2[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[N:9][C:7]=2[N:8]=1.[OH-].[Na+].[BH4-].[Na+]>CC(N(C)C)=O>[NH2:2][C:3]1[N:4]=[C:5]([NH2:15])[C:6]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9][C:7]=2[N:8]=1
Reactant: Nc1nc(N)c2cc(C=O)cnc2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2cc(CO)cnc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-diaminopyrido[2,3-d]pyrimidine-6-carboxaldehyde hydrochloride (200 mg, 0.884 mmol) in DMAC (40 ml) at 0° C. was treated with 1N NaOH (0.884 ml, 0.884 mmol) followed by a suspension of NaBH4 (16.7 mg, 0.442 mmol) in DMAC (1 ml). The solution was stirred at 25° C. for 30 minutes and evaporated to dryness under high vacuum. A stirred suspension of the residue in H2O (5 ml) was adjusted to pH 3 with 6N HCl, stirred for 5 minutes and adjusted to pH 7 with 1N NaOH. The precipitate was collected by filtration, washed with H2O and dried in vacuo (P2O5); yield 121 mg (51%); mass spectrum, m/e 191 (M)+, 87 (M)+ for DMAC, 36 (M)+ for HCl; λmax nm (ε×10-3): 0.1N HCl-274 (6.91), 318 (8.21), 330 sh (7.17), 362 (1.77); pH 7-248 (18.1), 271 (9.85), 338 (6.52); 0.1N NaOH-248 (19.7), 271 (10.3), 345 (7.14).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.CCN(C(C)C)C(C)C.[CH2:30]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=[C:44]=[O:45])[CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClCCl>ClCCCl.O>[CH2:30]([C:37]1[CH:38]=[C:39]([NH:43][C:44]([N:16]2[CH2:15][C:14]3[CH:13]=[N:12][C:11]4[NH:10][N:9]=[CH:8][C:20]=4[C:19]=3[CH2:18][CH2:17]2)=[O:45])[CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1nc2[nH]ncc2c2c1C[NH2+]CC2
Reactant: O=C=Nc1cccc(Cc2ccccc2)c1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cc2ccccc2)c1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate (0.08 g, 0.2 mmol) in 1,2-dichloroethane (2 mL) was added Hunig's Base (0.2 mL) followed by 1-benzyl-3-isocyanatobenzene (40 μl, 0.2 mmol). The mixture was stirred at room temperature for 2 hours before being diluted with water (50 mL) and extracted with dichloromethane (2×50 mL). The organic extracts were dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale yellow oil. A minimum amount of dichloromethane was added and N-(3-benzylphenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide crystallized out as a white solid (0.038 g, 36%). M.p.=175-178° C. 1H NMR (DMSO-d6) 400 MHz δ 8.66 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.33-7.13 (m, 8H), 6.83 (d, J=7.6 Hz, 1H), 4.75 (s, 2H), 3.88 (s, 2H), 3.80 (d, J=5.2 Hz, 2H). LCMS [M+H]: 384.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Zn])#[N:2].[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](Cl)=[O:16]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[C:1]#[N:2])=[O:16]
Reactant: N#Cc1c(F)cccc1[Zn]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1C(=O)c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of 2-cyano-3-fluorophenylzinc (80.0 mL, 40.0 mmol, 0.5 M in THF), tetrakistriphenylphosphine palladium(0) (2.3 g, 2.0 mmol) was added in small portions at 0° C. A solution of 3-bromo-4-fluorobenzoyl chloride (10.0 g, 42.1 mmol) in anhydrous THF (20 mL) was then added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched by addition of water (150 mL) and the resulting mixture was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using 30% ethyl acetate in hexanes to afford the title compound (7.90 g, 61% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=O)[CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][NH:30][C:31]([NH:33][OH:34])=[NH:32].[ClH:35]>C(O)C>[ClH:35].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=[N:29][NH:30][C:31](=[NH:32])[NH:33][OH:34])[CH2:7]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccco1)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccco1)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-furyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (227 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. The residue in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 3 hours and cooled, and crystals precipitated while stirring was filtered, washed with ethanol and dried to give 7-(2-furyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 97) (154 mg) as pale yellow crystals.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[OH:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.Br[CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CCCCCC.O1CCCC1.O.C(O)(=O)C>[OH:13][C:14]1[CH:18]=[C:17]([CH2:19][CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[O:16][N:15]=1
Reactant: Cc1cc(O)no1
Reactant: BrCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Oc1cc(CCCCOC2CCCCO2)on1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
13.95 ml of a 15% by weight solution of butyllithium in hexane were added dropwise, at -25° to -15° C., to a solution of 3.08 ml of diisopropylamine in 100 ml of tetrahydrofuran. The mixture was stirred at -20° C. for 15 minutes, after which a solution of 0.990 g of 3-hydroxy-5-methylisoxazole in 10 ml of tetrahydrofuran was added to the mixture at -20° to -10° C. over a period of 10 minutes. The mixture was then stirred at -10° C. for 30 minutes, after which it was cooled to -50° C., and then 3.35 g of 1-bromo-3-(2-tetrahydropyranyl)oxypropane were added to it all at once. The mixture was then stirred at 15°-20° C. for 2 hours, after which it was mixed with 1.20 ml of acetic acid. It was then poured into water. The organic layer was separated and the aqueous layer was adjusted to a pH value of 3 by adding 10% w/v aqueous hydrochloric acid followed by extraction twice with diethyl ether. The combined organic layer and extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give a residue, which was subjected to column chromatography through 60 g of silica gel. 1.720 g of the title compound was obtained, as a colorless oil, from the fractions eluted with mixtures of ethyl acetate and hexane ranging from 1:2 to 1:1 by volume.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]=S)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]3[CH:43]=[CH:42][C:29]4[N:30]=C(NC5N(C(C)C)C=CN=5)[NH:32][C:28]=4[CH:27]=3)=[O:25])[CH:21]=2)[CH:16]=[N:15]1>CN(C=O)C.C1COCC1>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]3[CH:43]=[CH:42][C:29]4[N:30]=[C:12]([NH:11][C:4]5[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH2:9][CH3:10])[NH:32][C:28]=4[CH:27]=3)=[O:25])[CH:21]=2)[CH:16]=[N:15]1
Reactant: CCc1cccc(CC)c1N=C=S
Reactant: CC(C)n1ccnc1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1

Procedure:
A solution of 1,3-diethyl-2-isothiocyanatobenzene (0.5 mmol) in 1:1 DMF/THF (2 mL) was reacted with 3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-(2,6-diethylphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide. MS: m/z 425 (M+H)+.