Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:24])[CH3:23]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) in DMF (10 mL) was added cesium carbonate (5.04 g, 15.46 mmol) and 2-iodopropane (2.58 mL, 25.8 mmol). The mixture was heated at 100° C. overnight. After cooling to RT, H2O (300 mL) was added and the aqueous layer was extracted with EtOAC (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered, and solvent was removed in vacuo. The resulting crude material was reconstituted in MeOH (1.0 mL) and purified by HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C12H21BN2O2, 237; found 237.
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][CH3:21])[N:15]=2)[CH:11]=1>C(OCC)(=O)C.[Cu](I)I>[CH2:20]([N:14]1[CH:13]=[C:12]2[C:16]([C:17]([CH3:19])=[CH:18][C:10]([NH2:2])=[CH:11]2)=[N:15]1)[CH3:21]
Reactant: CN1CCCC1=O
Reactant: CCn1cc2cc(Br)cc(C)c2n1
Agent: I[Cu]I
Agent: N
Solvent: CCOC(C)=O
Product: CCn1cc2cc(N)cc(C)c2n1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Copper oxide (I) (60 mg), NMP (2 mL), and concentrated aqueous ammonia (2 mL) were added to 5-bromo-2-ethyl-7-methyl-2H-indazole obtained in the above-described Step 1 (446 mg), and the reaction solution was stirred in a microwave reactor at 100° C. for 10 hours. The reaction solution was cooled to room temperature, and diluted with ethyl acetate. Thereafter, the reaction solution was washed successively with water four times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-ethyl-7-methyl-2H-indazol-5-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[CH:10][C:9]=2[C:24]#[N:25])=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[C:24]([C:9]1[CH:10]=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)=[CH:3][CH:4]=1)#[N:25]
Reactant: OB(O)c1ccco1
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(Br)cc2)cc1F
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(-c3ccco3)cc2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 5 using 5-(4-bromophenyl)-4-cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide, 2-furanboronic acid instead of 3-thienylboronic acid.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[F:20][C:21]1[CH:26]=[C:25]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert-butylate were dissolved in 90 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with aq. 16% strength. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). Following combination of the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.9 g (44.9%) of the desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][O:11][CH2:12]Cl)=[CH:5][N:4]=1.Cl.[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][O:11][CH2:12][N:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]2=[O:22])=[CH:5][N:4]=1
Reactant: CSc1ncc(COCCl)c(C)n1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(COCn2cc(Cl)cnc2=O)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylthio-4-methyl-5-(chloromethyloxymethyl)pyrimidine (see Preparation 11) (2.7 mmol) in dichloromethane (5 ml) was added dropwise with stirring at room temperature to a solution of 5-chloropyrimidin-2-one hydrochloride (2.7 mmol) and triethylamine in dichloromethane (0.76 ml). The mixture was stirred for 24 hours at room temperature before the solvent was distilled off. The residue was triturated with water, extracted into chloroform and the dried (MgSO4) solution evaporated. yield 0.55 g (65%). 1H NMR (CDCl3): δ2.42 (4-Me), 2.55 (SMe), 4.65 (CH2Pyr), 5.32 (CH2O), 7.80 and 8.42 (H-4, H-6, J 3 Hz), 8.20 (H-6').
Reaction SMILES: C(O[C:4](=[O:12])[CH:5]([Na])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[H-].[Na+].C(OCC)(=O)CC(OCC)=O.[CH2:26]([O:33][C:34]([N:36]1[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P(=O)(O)(O)O>O1CCCC1>[CH2:9]([O:8][C:6]([CH:5]1[CH2:38][CH2:37][N:36]([C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:4]1=[O:12])=[O:7])[CH3:10]
Reactant: CCOC(=O)C([Na])C(=O)OCC
Reactant: O=C(OCc1ccccc1)N1CC1
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Reaction time: 22 h

Procedure:
To a solution of sodiomalonic acid diethyl ester prepared from sodium hydride (704 mg), diethyl malonate (3 ml), and tetrahydrofuran (10 ml) is added aziridine-1-carboxylic acid benzyl ester (1.8 g). After 22 hours at room temperature, the mixture is neutralized with 10% phosphoric acid, washed with water, dried and concentrated to give 1-carbobenzoxy-2-oxopyrroidine-3-carboxylic acid ethyl ester (1.85 g). Oil. IR (CHCl3) ν: 1785, 1730 cm-1.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]([O-:9])=O)=[CH:5][C:4]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[O:3]1.[NH2:15][C:16]1[CH2:24][C:20]2([CH2:23]C[CH2:21]2)[CH2:19][C:18](=[O:25])[CH:17]=1>>[OH:9][C:7]1[C:6]2[C:2](=[O:1])[O:3][C:4]3([CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]=2[C:17]2[C:18](=[O:25])[CH2:19][C:20]([CH3:23])([CH3:21])[CH2:24][C:16]=2[N:15]=1
Reactant: O=C([O-])C1=CC2(CCOCC2)OC1=O
Reactant: NC1=CC(=O)CC2(CCC2)C1
Product: CC1(C)CC(=O)c2c(nc(O)c3c2C2(CCOCC2)OC3=O)C1

Procedure:
Obtained by starting from 2-oxo-1,8-dioxaspiro[4.5]dec-3-ene-3-carboxylate and 8-aminospiro[3.5]non-7-en-6-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[NH2:25][C:26]1[N:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:29]3[CH:28]=[CH:27][C:26]([NH2:25])=[N:31][CH:30]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (87 mg, 0.5 mmol) according to general procedure II. Obtained as a red solid (48 mg, 22%). MS (EI) 429.1 [(M)+]; mp 164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)c5ccc(Cl)cc5)cc4c3)c2cc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.110 g, 0.31 mmol) in 10 ml of CH2Cl2 was added K2CO3 (0.086 g, 0.62 mmol). The mixture was cooled to 0° C. and 4-chlorobenzoyl chloride (44 mL, 0.34 mmol) was added. The solution was stirred for 16 h and allowed to gradually warm up to RT. The reaction was diluted with water and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 485.0 (M+1). Mass Calc'd for C29H21ClN2O4: 484.937.
Reaction SMILES: [Na+:1].[C:2](/[C:6](=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH2:7][S:8]([O-:11])(=[O:10])=[O:9])([O:4][CH3:5])=[O:3].[H][H]>[Ni].CO.O>[Na+:1].[C:2]([CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8]([O-:11])(=[O:10])=[O:9])([O:4][CH3:5])=[O:3]
Reactant: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)[O-]
Reaction time: 24 h
Yield: 88 %

Procedure:
To the 8 L of 1:1 methanol/water mixture containing the resultant compound from Example 1C was added 60 g of W-24 raney nickel. The resulting suspension was pressurized under 50 psi of hydrogen and was allowed to shake on a Parr shaker for 24 h, at which time an additional 20 g of raney nickel catalyst was added. After 6 h under 50 psi of hydrogen, the catalyst was removed by filtration and the solution was concentrated to dryness. To the dry white solid was added ethyl acetate (6 L) and heptane (4 L) and the solution was vigorously stirred with a mechanical stirrer overnight. The white suspension was removed by filtration yielding 530 g (88%) of the desired product as an amorphous powder that was contaminated with approximately one equivalent of NaBr. The compound was used without any additional purification: IR (KBr) 1740, 1215, 1050 cm-1. 1H NMR (DMSO D-6) δ 2.48-2.54 (m, 1H), 2.74-2.87 (m, 2H), 2.91-3.04 (m, 2H), 3.48 (s, 3H), 7.12-7.32 (m, 5H); 13C NMR (75 MHz, D2O/DMSO D-6) δ 38.18, 44.80, 52.67, 52.82, 127.42, 129.13, 129.34, 138.14, 176.84.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>C(O)C.C(OCC)(=O)C>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(CN)cc1OC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3,4-dimethoxy-benzylamine (100 g) and ethyl acrylate (65 ml) in ethanol (2L) and cylcohexane (1L) was stirred at room temperature for 20 hours then evaporated to give the title compound as a colourless oil (154 g). MS: 268 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]([C@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]1[CH2:15][C@H:14]1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: ClC[C@@H]1CO1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@@H]3CO3)ccc2s1
Reaction time: 8 h

Procedure:
A mixture of 2-methylbenzothiazol-5-ol, a compound of formula (1) (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin, a compound of formula (2) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml), was heated to reflux and allowed to stir overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated (in vacuo), to yield an oil. The oil was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to yield 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole as a white solid (6.2 g, 28 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:17]=1>CN(C=O)C.[Cu]I.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>[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([NH:26][C:18]2[N:17]=[C:16]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:9]3([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]3)[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][N:19]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.120 g, 0.648 mmol), 4-chloro-N-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine A68 (0.197 g, 0.648 mmol), CuI (0.012 g, 0.065 mmol), t-Bu3PHBF4 (0.019 g, 0.065 mmol) and PdCl2(PPh3)2 (0.023 g, 0.032 mmol) in DMF (3 mL) was bubbled with N2 for 5 minutes. Et3N (1 mL) was added and the reaction mixture was stirred in the microwave at 120° C. for 15 minutes. The volatiles were removed in vacuo and the black residue was adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A73 as a yellow solid (0.229 g, 78%). LCMS-D: rt 3.47 min; m/z 454 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:3]1[CH2:4][CH2:5]2)=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[N:28][CH:27]=[C:26]([Cl:30])[N:25]=2)[CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1>O>[Cl:30][C:26]1[N:25]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:7](=[O:9])[CH:6]4[C:2]([CH3:1])([CH3:12])[CH:3]([CH2:4][CH2:5]4)[C:10]3=[O:11])[CH2:23][CH2:22]2)[CH:29]=[N:28][CH:27]=1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3cncc(Cl)n3)CC1)C2=O

Procedure:
2,2-Dimethylcyclopentane-1,3-dicarboxylic anhydride (1.68 g., 10 mmole) and 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine (2.97 g., 11 mmole) were combined in 500 ml. of xylene and refluxed for 48 hours with Dean-Stark water removal. Concentration in vacuum, column chromatography on 100 g. of silica gel with chloroform, and recrystallization from 50 ml. of isopropanol with addition of 4N isopropanolic HCl gave 0.55 g. of the title compound as the monohydrochloride; m.p. 210° C. (d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1cccnn1
Product: N=C(NCCNCc1cccnn1)N[N+](=O)[O-]

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine. Treatment with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][F:15])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N+:12]=[N-:13])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[Cl:23][CH:24]([Cl:30])[C:25](OCC)=[O:26]>CO>[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@H:2]([NH:1][C:25](=[O:26])[CH:24]([Cl:30])[Cl:23])[CH2:14][F:15])=[CH:10][CH:9]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](N)CF)cc1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To the stirred solution of (1R,2R)-2-Amino-1-(4-azido-phenyl)-3-fluoro-propan-1-ol (600 mg, 2.83 mmol) in methanol (6.5 mL) is added triethyl amine (0.57 g, 5.64 mmol) and ethyl dichloroacetate (0.88 g, 5.60 mmol). Resulting reaction mixture is stirred under nitrogen at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 0.5% methanol in dichloromethane to afford the title compound (150 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 4.40-4.41 (m, 1H), 4.24-4.26 (m, 0.5H), 4.36-4.38 (m, 0.5H), 4.52-4.54 (m, 0.5H), 4.64-4.66 (m, 0.5H), 4.84 (t, 1H, J=3.64 Hz), 5.96 (d, 1H, J=4.24 Hz), 6.49 (s, 1H), 7.05 (d, 2H, J=8.48 Hz), 7.38 (d, 2H, J=8.44 Hz), 8.58 (d, 1H, J=8.98 Hz). LC-Ms (m/z): [M−H]=318.8.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2].[CH2:12]=O>C1N2CCN(CC2)C1.C1(C)C=CC=CC=1>[C:1]([C:3](=[CH2:12])[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: CC(C)(C)COC(=O)CC#N
Reactant: C=O
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: C=C(C#N)C(=O)OCC(C)(C)C

Procedure:
46.5 (0.3 mole) of neopentyl α-cyanoacetate, 8.1 g (0.27 mole) of paraformaldehyde, 140 g of toluene and 46.5 mg of triethylenediamine were reacted together under reflux and water was removed by azeotropic distillation. Then, 23.5 g of dioctyl phthalate, 0.465 g of hydroquinone and 0.93 g of phosphorus pentoxide were added and depolymerization allowed to take place at 150°-210° C. under a reduced pressure tO afford 21.65 g of crude neopentyl α-cyanoacrylate. Redistillation thereof afforded (8.3 g of neopentyl α-cyanoacrylate (b.p. 65°-67° C./2 mmHg, m.p. 40°-41° C., yield 36%).
Reaction SMILES: [CH2:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:4]([C:5](=[O:14])[CH2:6][CH2:7]3)[C:3](=[O:15])[CH2:2]1.Cl.[C:17]1([CH2:23][OH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][O:24][C:3](=[O:15])[CH2:2][CH2:1][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[NH:4][C:5](=[O:14])[CH2:6][CH2:7]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCc2cccc3c2N1C(=O)CC3
Agent: Cl
Product: O=C1CCc2cccc(CCC(=O)OCc3ccccc3)c2N1

Procedure:
A solution of 1,2,6,7-tetrahydro-3H,5H-benzo[ij]-quinolizine-3,5-dione (20.1 g, 0.1 mole) in phenylmethanol (200 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the starting dione can no longer be detected by thin layer chromatography). The solution is cooled and concentrated at reduced pressure. The product is purified by flash chromatography to yield 1,2,3,4-tetrahydro-2-oxo-8-quinoline propanoic acid phenylmethyl ester.
Reaction SMILES: Br[C:2]1[S:16][C:5]2=[N:6][C:7]([CH3:15])=[CH:8][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:7]1[N:6]=[C:5]2[S:16][C:2]([C:28]3[CH:29]=[N:25][NH:26][CH:27]=3)=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:4]2=[C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
Temperature: 130 °C
Yield: 34.1 %

Procedure:
To a suspension of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}methanesulfonamide (Example 97) (109 mg, 0.255 mmol), 1H-pyrazol-4-ylboronic acid (60 mg, 0.536 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-dioxane (1.5 mL) and water (0.6 mL), was added tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for 1 h, followed by the addition of another portion of 1H-pyrazol-4-ylboronic acid (41 mg, 0.366 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for another 1 h and was then directly loaded onto a silica column, eluting with a gradient of 0-75% of ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 413 [M−1]−, Rt 0.97 min (acidic).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]3[C:22]=2[CH2:23][CH2:24][CH2:25][NH:26]3)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[C:1]([N:26]1[C:27]2[C:22](=[C:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH3:5])[CH2:14][CH2:15]3)[CH:30]=[CH:29][C:28]=2[OH:31])[CH2:23][CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3C(C)=O)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 1.45 ml of acetyl chloride is 20 ml of tetrahydrofuran is added at 5° C. to a solution of 7.34 g of 5-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-8-hydroxy-1,2,3,4-tetrahydro quinoline in 140 ml of anhydrous tetrahydrofuran containing 2.8 ml of triethylamine. This is stirred for 2 hours at 5° C. and then for 1 hour at room temperature. Then, the insoluble substance is filtered off and concentrated to dryness under reduced pressure. The residue is purified by chromatoflash on 750 g of silica (70-230 mesh) by eluating with the mixture CH2Cl3 /CH3OH (95/5).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:34](O)[CH3:35]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:12]([O:14][CH2:34][CH3:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)C(CCCCNc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CCCCNc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
5 g of 2,6-bis[(4-nitrophenyl)amino]hexanoic acid dissolved in 50 ml of ethanol and 1.5 ml of sulphuric acid are introduced into a 100 ml three-necked flask equipped with a condenser and a thermometer, and the mixture is then refluxed overnight.