Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:72][CH2:73]C4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH:100]1[C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][C:103]=2[N:102]=[C:101]1[CH2:109]CN>>[ClH:45].[NH:100]1[C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][C:103]=2[N:102]=[C:101]1[CH2:109][CH2:73][NH:72][C:70]([NH:69][C@@H:66]1[CH2:67][CH2:68][N:64]([C:62]2[N:61]=[C:60]3[C:56]([N:57]=[CH:58][N:59]3[C@@H:80]3[CH2:84][C@H:83]([N:85]4[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]4)[C@@H:82]([OH:92])[C@H:81]3[OH:93])=[C:55]([NH:54][CH2:53][CH:52]([C:94]3[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:63]=2)[CH2:65]1)=[O:71]
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCCc1nc2ccccc2[nH]1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCCc6nc7ccccc7[nH]6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 2-(1H-benzoimidazol-2-yl)-ethylamine. MS (ES+) m/e 783.55 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+].O.Cl>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH3:15])[CH3:14])=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: CC(C)(c1ccccc1)c1ccc(-c2cnn(C(N)=O)c2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(c1ccccc1)c1ccc(-c2c[nH]nc2N)cc1
Yield: 75.5 %

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-[4-(2-phenylpropan-2-yl)phenyl]pyrazole (1.5 g) in methanol (20 ml) was added 5N sodium hydroxide solution (2 l), and the mixture was refluxed. To the mixture was added water (50 ml) under ice-cooling, and the mixture was neutralized (pH 7 to 8) with 10% hydrochloric acid solution, and was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (chloroform:methanol=1:3) to give the title compound (980 mg, 75.5%).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S].[C:27](=[S:29])=[S:28]>[OH-].[Na+].O.C(O)(=O)C>[C:4]([C:3]1[C:2]2[S:28][C:27]([SH:29])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Agent: [S-2]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc2nc(S)sc12
Temperature: 45 °C

Procedure:
2-Chloro-3-nitrobenzoic acid (8.06 g, 0.04 mol) in 1N sodium hydroxide (50 mL) was added to a polysulfide solution made from sodium sulfide nonahydrate (28.82 g, 0.12 mol) and sulfur (9.60 g, 0.30 mol) in water (30 mL). The resulting mixture was stirred and heated at reflux for 5.5 hours. The reaction mixture was cooled to 45° C., treated with carbon disulfide (4.81 mL, 0.08 mL), and stirred at 45° C. for 20 hours. The mixture was cooled in an ice bath and neutralized by slowly adding acetic acid (7 g). The solid precipitate was collected, washed with ice-cold water, suspended in saturated sodium carbonate solution (100 mL), and filtered to remove insolubles. The filtrate was acidified with acetic acid (33 g) and filtered to collect the insoluble material. The filter cake was dried under vacuum to afford crude 7-carboxy-2-mercaptobenzothiazole (0.70 g) as a brownish gray solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:22][C:21]=2[CH3:36])=[O:19])=[C:14]([Cl:37])[CH:13]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[Cl:37][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][C:15]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:22][C:21]=1[CH3:36])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: Cc1cc(OCCOC2CCCCO2)ccc1C(=O)c1ccc(N)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OCCOC2CCCCO2)ccc1C(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-Iodo-2-nitro-benzene (1.38 g, 5.54 mmol) was dissolved in 40 mL dry 1,4-dioxane under an argon atmosphere. Compound 471 (1.77 g, 4.54 mmol) was added and dissolved in the solvent. Rac-BINAP (106 mg, 0.17 mmol), Pd2(dba)3 (104 mg, 0.11 mmol) and Cs2CO3 (2.07 g, 6.30 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 100° C. for 24 h. The reaction mixture was poured into a mixture of EtOAc and water. The aqueous phase was washed with more EtOAc. The organic phases were combined and washed with brine, dried (MgSO4), filtered and then purified by flash chromatography using EtOAc/petroleum ether 1:5 as the eluent to afford the title compound.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:21][CH:22]=1>C1(C)C=CC=CC=1.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>[CH:1]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:21][CH:22]=1)=[CH2:2]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Yield: 80.4 %

Procedure:
Tributyl(vinyl)stannane (50 g, 0.16 mol), Pd(Ph3P)4 (3.3 g, 2.9 mmol) and a catalytic amount of 2,6-t-butyl-4-methylphenol was added to a solution of N-(5-bromopyridin-2-yl)pivalamide (36 g, 0.14 mol) in toluene. The reaction mixture was heated at reflux for 48 h. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford N-(5-vinylpyridin-2-yl)pivalamide (23 g, 80% yield). 1H NMR (CDCl3, 300 MHz) δ 8.24-8.20 (m, 2H), 8.02 (br s, 1H), 7.77 (dd, J=8.7 and 2.4, 1H), 6.65 (dd, J=17.7 and 10.8, 1H), 5.73 (d, J=17.7, 1H), 5.29 (d, J=10.8, 1H), 1.32 (s, 9H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[CH2:16][C@H:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC(N(C)C)=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C@@H:13]3[CH2:14][C@H:15]([CH2:17][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ccc(CN4CCCC4)cc3)C2)cc1
Solvent: CC(=O)N(C)C
Product: c1cc([C@H]2C[C@@H](CN3CCOCC3)C2)ccc1CN1CCCC1
Temperature: 100 °C

Procedure:
To a stirring cis-toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (example 47) (0.41 g, 1.0 mmol) in DMA (5 mL) was added an amine for example morpholine (0.18 g, 2 mmo). The reaction was then heated to 100° C. (oil bath). After 4 hr the reaction was cooled to rt and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography, using a 45 g ISCO column, eluting with a gradient of 5%, 10%, 20%, 60% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were collected and concentrated to yield the title compound (214 mg) as the TsOH salt. This material was free based by stirring in solid K2CO3 and MeOH for 2 hours. After 2 hr the methanolic solution was concentrated, diluted with CH2Cl2, filtered, and concentrated under reduced pressure to give the free base. The HCl salt was made by taken the freebase up in EtOAc and then adding a solution of HCl (2 eq, 1 M HCl, THF) to give a colorless solid.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.CC(=O)CCC(=O)C.[NH2:20][C:21]1[N:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1.C>C1(C)C=CC=CC=1>[Cl:27][C:24]1[N:23]=[N:22][C:21]([N:20]2[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]2[CH3:2])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Cl)nn1
Agent: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Cl)nn1
Temperature: 140 °C

Procedure:
A mixture of p-TSA (117 mg, 0.618 mmol), 2,5-hexanedione (4.36 mL, 37.1 mmol) and 3-amino-6-chloropyridazine (4.00 g, 30.9 mmol) in toluene (150 mL) was heated at 140° C. for 5 h in a round bottom flask equipped with a condenser and Dean-Stark apparatus. The reaction mixture was cooled to rt and charcoal was added. The mixture was filtered through CELITE and concentrated in vacuo to afford the title compound i-6a. m/z (ES) 208 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]([C:5]1([N:16]([CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH3:17])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4]>O1CCOCC1>[Cl:38][C:34]1[C:33]([F:39])=[C:32]([NH:31][C:22]2[C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([CH2:18][N:16]([CH3:17])[C:5]4([C:3]([NH2:2])=[O:4])[CH2:8][NH:7][CH2:6]4)[CH:20]=3)[N:25]=[CH:24][N:23]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reaction time: 8 h
Yield: 132.5 %

Procedure:
A solution of concentrated hydrochloric acid (5 ml) in 1,4-dioxan (25 ml) was added dropwise to a solution of tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate (303 mg, 0.56 mmol) in 1,4-dioxan (6 ml). The reaction mixture was stirred overnight, then concentrated under reduced pressure. The residues were triturated with a mixture of methanol/dichloromethane/diethylether to give the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide as a solid (330 mg, 100%); 1H NMR Spectrum: (DMSO-d6) 2.19 (s, 3H), 3.73 (s, 2H), 3.95 (brd, 2H), 4.04 (s, 3H), 4.13 (brd, 2H), 7.38 (m, 2H), 7.56 (t, 1H), 7.61 (s, 1H), 7.66 (s, 1H), 7.75 (brs, 1H), 8.92 (s, 1H), 8.92 (brs, 1H), 9.30 (s, 1H), 9.80 (brs, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=1[OH:11]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1O
Temperature: 0 °C
Yield: 72 %

Procedure:
A 50 ml round-bottom flask equipped with a stir bar under a dry nitrogen atmosphere was charged with 4-methylsalicylic acid (1.5 g, 10.0 mmoles, 1.0 eq) followed by dry MeOH (15 ml). The reaction mixture was cooled to 0° C. on an ice bath and neat SOCl2 (1.1 ml, 15.0 mmoles, 1.5 eq) was added dropwise. The reaction was allowed to warm to room temperature and then stirred at reflux for 5 hrs. After that time, excess MeOH was removed in vacuo, the residue dissolved in EtOAc and extracted with saturated NaHCO3, the organic layer was dried with MgSO4 and filtered. Removal of excess solvent from the filtrate in vacuo provided 1.20 g (72%) of the title compound as a clear oil. (1H CDCl3, 400 MHz): δ 10.71 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 6.75 (s, 1H), 6.69 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:19])[C:11](=[O:18])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:43]1([CH2:46][O:47][NH2:48])[CH2:45][CH2:44]1.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[CH:43]1([CH2:46][O:47][NH:48][C:15]([C:14]2[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH3:19])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[O:17])[CH2:45][CH2:44]1
Reactant: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Reactant: NOCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)NOCC2CC2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.022 g, 0.064 mmol), EDCl (0.019 g, 0.097 mmol), and HOBt (0.019 g, 0.097 mmol) in DMA (1 mL) was stirred for 30 minutes at room temperature under N2. O-Cyclopropylmethyl-hydroxylamine (0.017 g, 0.19 mmol) was added followed by Et3N (0.022 mL, 0.016 g, 0.16 mmol). After the reaction mixture was stirred for 16 hours at room temperature, it was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.015 g (57%) pure desired product as a yellow solid. MS APCI (−) m/z 410, 411 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 9.81 (s, 1H), 7.58 (m, 2H), 7.28 (d, 1H), 6.82 (t, 1H), 6.17 (d, 1H), 3.46 (d, 2H), 3.22 (s, 3H), 0.99 (m, 1H), 0.48 (m, 2H), 0.18 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([NH2:21])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc([N+](=O)[O-])cc2Cl)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cc2Cl)CC1
Yield: 62.8 %

Procedure:
Place 4-(3-chloro-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.09 g, 9.01 mmol) in methanol (50 mL). Add nickel(II) chloride hexahydrate (10.7 g, 45.1 mmol) and cool the reaction to 0° C. Add sodium borohydride (5.11 g, 135.15 mmol) in portions and stir at 0° C. for 2 hours. Add CH2Cl2 and filter through a pad of Celite®. Wash filter cake with CH2Cl2 and collect filtrate. Add saturated aq. sodium bicarbonate solution to the filtrate and separate organic layer. Extract aqueous layer with CH2Cl2 (2×30 mL). Combine organic extracts, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-70% EtOAc:hexane to yield 1.77 g (63%) of the title compound. MS(ES): m/z=311.2 [M−H].
Reaction SMILES: C(N(CC)CC)C.C(O[CH:13]=[CH:14][C:15](=O)[C:16]([O:18][CH3:19])=[O:17])CCC.Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>C(#N)CC>[NH2:25][C:23]1[N:24]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:13][N:22]=1
Reactant: CCCCOC=CC(=O)C(=O)OC
Reactant: N=C(N)N
Agent: Cl
Solvent: CCC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(N)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Triethylamine (29 mL, 210 mmol) was added to a suspension of methyl 4-butoxy-2-oxo-3-butenate (37 g, 200 mmol, JP-A-2003-89690) and guanidine hydrochloride (23 g, 240 mmol) in propionitrile (50 mL), and the mixture was stirred for 4 hours at 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18 g as the mixture of the title Reference Compound and the butyl ester form of the title Reference compound as a gray-white solid (Yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8]1)=S.FC1C=C(C=CC=1F)C(N1CCCC(C2C=CC=CC=2)=N1)=S.ClC1C=C(C=CC=1Cl)C(N1CCCC(C2C=CSC=2)=N1)=[O:50].ClC1C=C(C=CC=1Cl)C(N1CCCC(C2SC=CC=2)=N1)=S.ClC1C=C(C=CC=1Cl)C(N1CCCC(C2C=CSC=2)=N1)=S>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8]1)=[O:50]
Reactant: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccccc2)=N1
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Agent: Fc1ccc(C(=S)N2CCCC(c3ccccc3)=N2)cc1F
Agent: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cccs2)=N1
Agent: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccccc2)=N1

Procedure:
1-(3,4-dichlorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine; 1-(3,4-difluorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine; 1-(3-bromo-4-fluorothiobenzoyl)-3-phenyl-1,4,5,6-1tetrahydropyridazine; (R,S)-(3,4-difluorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine; (R,S)-1-(3,4-dichlorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine; (R,S)-1-(3,4-dichlorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine; (R,S)-1-(3,4-difluorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine 1-(3,4-dichlorobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine and 1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:17]#[N:18].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:21]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=4[F:13])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Temperature: 77.5 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, step 1, 0.857 g), 3-fluoro-4-(piperazin-1-yl)benzonitrile (1.039 g), triethylamine (0.75 mL), and THF (6 mL) is stirred for 3 h at 75-80° C. The mixture is then concentrated under reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96). The appropriate fractions are combined and concentrated. Ethyl ether is added to the residue and the resulting solid is collected, washed with additional ethyl ether, and dried under reduced pressure to give 1.25 g of the title compound. A portion of this material is recrystallized from ethyl acetate; mp 132-133° C. ; IR (mineral oil) 1255, 1513, 1246, 801, 1504 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.26, 3.77, 6.90, 7.13, 7.25, 7.34, 7.53, 8.13.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:19]([C:22]1[C:23]([OH:50])=[C:24]([O:42][Si](C(C)(C)C)(C)C)[C:25](/[CH:28]=[CH:29]\[C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)=[CH:26][CH:27]=1)([O-:21])=[O:20].C(O)(=O)C>C1COCC1.C(OC)(C)(C)C>[N+:19]([C:22]1[C:23]([OH:50])=[C:24]([OH:42])[C:25](/[CH:28]=[CH:29]\[C:30]2[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=2)=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: COc1cc(/C=C\c2ccc([N+](=O)[O-])c(O)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COc1cc(/C=C\c2ccc([N+](=O)[O-])c(O)c2O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrabutylammonium fluoride (0.77 mL, 0.769 mmol, 1M in THF) was added to a solution of 46 (0.355 g, 0.769 mmol) and glacial acetic acid (0.04 mL, 0.769 mmol) in THF (4 mL) at rt. The reaction mixture was stirred at rt for 3 h then diluted with t-BuOMe and washed successively with water and brine. The organic layer was dried (Na2SO4) and evaporated to dryness to give a crude product which was purified by column chromatography (three times—first with: EtOAc:cyclohexane 3:7+1% acetic acid, then with neat CH2Cl2 and finally with CH2Cl2:methanol 40:1) to yield ZSB-83 (65 mg, 25%):
Reaction SMILES: [Li][NH2:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.C([O-])(O)=O.[Na+]>COCCOC>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([NH2:2])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: [Li]N
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
(CyPF-t-Bu)PdCl2 (7.30 mg, 1.00×10−2 mmol), LiNH2 (0.230 g, 10.0 mmol) and 4-t-butyl-1-bromobenzene (0.213 g, 1.00 mmol) were weighed into a 24 mL vial. DME (20.0 mL) was then added. The vial was sealed with a cap containing a PTFE septum, and the reaction mixture was stirred for 24 h at 80° C. The reaction mixture was allowed to cool to room temperature before pouring into ice water (20.0 mL). To this mixture was added HCl aqueous solution (10.0 mL, 1.0 M). The mixture was stirred at room temperature for 5 min and was then neutralized with a saturated solution of NaHCO3 (5.00-10.0 mL). After extraction with CH2Cl2 (3×20.0 mL), the organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude product isolated by eluting with hexane/ethyl acetate (80/20) to give 107.0 mg (72%) of 4-t-butylaniline as a pale yellow liquid.