Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH2:5][CH2:4]1.C(O)(=O)C.C(N(CC)CC)C.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH:35]=O)[CH3:30].C([BH3-])#N.[Na+]>C(O)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:35][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH2:7][CH2:8]1)[CH3:30]
Reactant: N#Cc1ccnc(NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-isonicotinonitrile dihydrochloride (43.0 mg, 0.18 mmol, 1.0 equiv; intermediate B15) in ethanol (2 mL), acetic acid (54.1 mg, 0.9 mmol, 5.0 equiv) and triethylamine (36.4 mg, 0.36 mmol, 2.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (36.1 mg, 0.22 mmol, 1.2 equiv; intermediate E10) and the mixture stirred at 50° C. After 1 h, sodium cyanoborohydride (13.8 mg, 0.22 mmol, 1.2 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 50° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.8 mg (3%) of the title compound. MS (ISP): 351.5 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cccc(F)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(F)c2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-fluorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-fluorophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH2:35][C@@H:36]([NH2:38])[CH3:37])[CH:34]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH2:35][CH:36]([NH:38][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:27][C:12]3=[CH:13][C:14]4[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=4[CH:19]=[C:11]3[N:10]=2)[CH3:37])[CH:34]=1
Reactant: CN(C)CCN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: Cc1ccc(F)cc1C[C@H](C)N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 84.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.05 g, 2.72 mmol), (S)-1-(5-fluoro-2-methylphenyl)propan-2-amine (0.55 g, 3.26 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a bown solid product, 1.18 g, 84.3% yield. MS: 517.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.23 (s, 1H), 10.86 (d, 1H, J=8.1 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.31-7.10 (m, 3H), 6.90-6.83 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.22-4.13 (m, 1H), 3.68 (t, 2H, J=6.5 Hz), 3.00 (d, 2H, J=6.9 Hz), 2.51-2.47 (m, 2H), 2.42 (s, 3H), 2.18 (s, 6H), 1.34 (d, 3H, J=6.3 Hz).
Reaction SMILES: [NH:1]1C2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[C:3](C=O)=[CH:2]1.FC1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.N1C=NN=N1.[N-]=[N+]=[N-].[Na+].N[OH:31]>>[CH3:20][CH2:19][C:16]1[C:17](=[O:31])[N:18]2[C:2]([CH:3]=[CH:4][CH:5]=[C:6]2[CH3:7])=[N:1][C:15]=1[CH3:14]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: NO
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1nnn[nH]1
Product: CCc1c(C)nc2cccc(C)n2c1=O

Procedure:
XO-CH145 was prepared by coupling of indole-3-carboaldehyde and 4-fluorobenzonitrile in a similar manner to the third step of the above 1. XO-CH147 was prepared by converting XO-CH145 into a tetrazole derivative using sodium azide, followed by cyanation using hydroxylamine to give XO-CH150 (the following scheme).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([NH2:37])[CH2:35][CH3:36]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:37][CH2:34][CH2:35][CH3:36])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CCCN
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and propylamine. ES-MS m/e (%): 428 (M+H+, 100).
Reaction SMILES: Cl.[CH3:2]N(/C(=C\C)/C(O)=O)C.C(Cl)(=O)C(Cl)=O.[CH3:17][NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH:22]=[CH:21][CH:20]=1.[CH3:46][N:47]1[C:51](=[O:52])[CH2:50][CH2:49][CH2:48]1>CC#N.CN(C=O)C.CCOC(C)=O>[CH3:2][N:47]([CH3:46])[CH2:48]/[CH:49]=[CH:50]/[C:51]([N:18]([CH3:17])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([NH:25][C:26]2[CH:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][CH:34]=3)[N:29]=[CH:28][N:27]=2)[N:24]=1)=[O:52]
Reactant: CN1CCCC1=O
Reactant: C/C=C(/C(=O)O)N(C)C
Reactant: CNc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)C/C=C/C(=O)N(C)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Reaction time: 0.5 h

Procedure:
To a solution of dimethylaminocrotonic acid hydrochloride (0.120 g, 0.72 mmol) in CH3CN (1.4 mL) was added DMF (1 drop) followed by oxalyl chloride (0.07 mL, 0.91 mmol) at 0° C. under nitrogen atmosphere. The reaction was allowed to stir at this temperature for 30 min and then at rt for 2 h. This acid chloride was added, drop wise, at 0° C. in to a stirred solution of N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.07 g, 0.18 mmol) in NMP (2.8 mL). The reaction was allowed to stir at 0° C. for 1 h, diluted with EtOAc (5 mL), and washed with 10% NaHCO3 (2 mL), water (2 mL) and brine (2 mL). drying over Na2SO4 followed by concentration under reduced pressure gave a residue which was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give (E)-4-(dimethylamino)-N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-79) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 2.05 (s, 6H), 2.91 (d, J=6 Hz, 2H), 3.27 (s, 3H), 6.08 (d, J=15.2 Hz, 1H), 6.65 (dd, J=5.6 & 14.8 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.97-7.00 (m, 4H), 7.10 (t, J=7.2 Hz, 1H), 7.20 (s, 1H), 7.35-7.39 (m, 2H), 7.46 (d, J=8 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.75 (t, J=8 Hz, 1H), 8.30 (s, 1H), 9.30 (s, 1H), 9.95 (s, 1H); LCMS: m/e 496 (M+1).
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[C:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[NH2:15][C:16]1[C:20](C#N)=[C:19]([CH3:23])[NH:18][N:17]=1>C(O)(=O)C>[CH3:23][C:19]1[C:20]([C:16]#[N:15])=[C:14]2[N:2]=[CH:3][C:4]([CH3:13])=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[N:17]2[N:18]=1
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: CC(=CN(C)C)C(=O)c1cccnc1
Solvent: CC(=O)O
Product: Cc1cnc2c(C#N)c(C)nn2c1-c1cccnc1

Procedure:
A mixture of 1.90 g. of 3-dimethylamino-2-methyl-1-(3-pyridyl)-2-propen-1-one and 1.22 g. of 3-amino-5-methylpyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 6 hours. The solvent is removed in vacuo and the residue partitioned between dichloromethane and saturated sodium bicarbonate solution. The dichloromethane layer is separated, dried over anhydrous sodium sulfate and passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 0.95 g. of the product of the example, m.p. 207°-209° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:9]=[C:8]([Cl:19])[CH:7]=1)=[O:4].C(O)(=O)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O.C([BH3-])#N.[Na+].Cl>C(OC)(OC)OC.O>[Cl:19][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@H](Cc3ccccc3)NCc3ccccn3)c2)ccn1
Yield: 75.5 %

Procedure:
(2S)-2-amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenylpropanamide (32 mg, 87 μmol) was dissolved in trimethyl thoformate (1 ml) and acetic acid (0.25 ml, 4367 μmol). To this was added picolinaldehyde (94 mg, 875 mmol). After 30 min sodium cyanoborohydride (82 mg, 1312 μmol) dissolved in trimethyl orthoformate (1 ml). After 1 h the reaction mixture was poured onto 1N HCl and water was added, the mixture was concentrated under reduced pressure. The resulting crude solid was dissolved in AcOH/DMSO and purified on Phenomenex Geminni C18 HPLC 50 mm×250 mm running ACN/Water/0.1% TFA in a linear gradient. The fractions containing the desired product were combined and concentrated to afford (2S)—N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(pyridin-2-ylmethylamino)propanamide (46) (30 mg, 75% yield). MS ESI (pos.) m/e: 457.1 (M+H). 1H NMR (500 MHz) (CDCl3) δ 10.13 (1H, s), 8.68 (1H, d, J=6.1 Hz), 8.50 (1H, d, J=5.4 Hz), 7.99 (1H, dt, J=1.2, 9.0 Hz), 7.88 (1H, s), 7.72-7.77 (3H, m), 7.47-7.53 (2H, m), 7.34 (1H, m), 7.16-7.24 (6H, m), 4.28-4.36 (3H, m), 3.30 (1H, dd, J=5.8, 13.9 Hz), 3.14 (1H, dd, J=7.8, 13.7 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:4]=1.[C-:27]#[N:28].[K+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[N:4]=[C:3]2[CH2:2][C:27]#[N:28]
Reactant: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(CC#N)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Yield: 60.9 %

Procedure:
In 1000 ml of dimethyl sulfoxide was dissolved 187.0 g of 3-chloromethyl-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole, followed by stirring at room temperature. To the solution was added 134.0 g of potassium cyanide, having been ground to powder in a mortar, followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into 15000 ml of water, and stirred for 1 hour. A precipitated solid was collected, washed with three 1000 ml portions of water, dissolved in 5000 ml of chloroform, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography using 2 kg of silica gel and chloroform:ethanol=50:1 and then 2 kg of silica gel and ethyl acetate:hexane=3:1, to yield 111.0 g of a pale brown solid. This solid was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CN.C1COCC1.C[CH2:19][N:20](CC)CC.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH3:19])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a stirred solution of 4-fluorobenzoic acid (200 mg, 1.43 mmol) in DCE (3 ml) at RT, was added a solution of methyl amine in THF (2 M, 1.43 mmol) and NEt3 (198 μl, 1.43 mmol) and allowed to stir for ca. 10 mins. HOBt (221 mg, 1.43 mmol) and DCC (295 mg, 1.43 mmol) were added and the reaction mixture heated at 70° C. for 3 h. After cooling to RT, the reaction mixture was washed with sat. NaHCO3 (5 ml) and the aqueous back extracted with DCM. The organics were combined, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH gradient 100:0 to 80:20) provided the title compound as off-white solid (137 mg, 63%).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:13][N:12]([C:14]3[N:15]4[C:19]([N:20]=[C:21]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=35)=[CH:18][CH:17]=[N:16]4)[CH2:11]2)=[O:9])[CH2:4]1)#[CH:2].C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:11][N:12]([C:14]3[N:15]4[C:19]([N:20]=[C:21]5[CH2:27][CH2:26][N:25]([CH3:30])[CH2:24][CH2:23][C:22]=35)=[CH:18][CH:17]=[N:16]4)[CH2:13]2)=[O:9])[CH2:4]1)#[CH:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)C1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C)CC4)C2)C1
Reaction time: 8 h

Procedure:
To 50 mg (0.14 mmol) of (3-Ethynyl-pyrrolidin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 2 mL of THF and 1 mL of puffer solution (pH 5) was added 11.3 μL (0.15 mmol) of formaldehyde (37% in water) and 35 mg (0.17 mmol) of sodium triacetoxyborohydride. Stirring was continued overnight, the reaction mixture diluted with 1 mL of water, filtered and purified by HPLC.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](B(O)O)[CH:19]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1>>[F:13][C:14]1[CH:19]=[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)=[N:3][CH:4]=2)[CH:17]=[N:16][CH:15]=1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: Cc1ccc(N)nc1
Reactant: OB(O)c1cncc(F)c1
Product: Cc1ccc(Nc2ncc(-c3cncc(F)c3)c3sc(C)nc23)nc1

Procedure:
The title compound, MS: m/e=352.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3-fluoro-5-pyridineboronic acid and 2-amino-5-methylpyridine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:29].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl>[Br:29][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1
Reactant: [Br-]
Reactant: CC(C)(C)c1cc2ccc3ccc(-c4ccccc4)c4ccc(c1)c2c34
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccccc4)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 2 h
Yield: 186.7 %

Procedure:
Next, a mixed solution of 1.5 g of 7-t-butyl-1-phenylpyrene, 25 ml of dichloromethane and 8 ml of methanol was cooled to 0° C. under a nitrogen gas stream and then 1.7 g of benzyltrimethylammonium tribromide dissolved in 5 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 2 hours and 20 ml of water was poured into the solution, followed by extraction with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. To the resulting solid, 10 ml of methanol was added, followed by standing overnight. The precipitated solid was filtered and then vacuum-dried to obtain 1.9 g of 1-bromo-7-t-butyl-3-phenylpyrene.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19].[CH2:20]1[O:22][CH2:21]1.[C:23](O)(=[O:25])[CH3:24]>O>[OH:25][CH2:23][CH2:24][N:1]([CH2:21][CH2:20][OH:22])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19]
Reactant: CC(=O)O
Reactant: COCCOCCOc1cc(C(=O)OC)ccc1N
Reactant: C1CO1
Solvent: O
Product: COCCOCCOc1cc(C(=O)OC)ccc1N(CCO)CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
Methyl 4-amino-3-(2'-(2"-methoxyethoxy)ethoxy)benzoate (5.0 g, 18.6 mmol) and ethylene oxide (8.8 g, 200 mol) were dissolved in 150 mL acetic acid to form a reaction mixture. The mixture was stirred at room temperature for 12 hours. It was diluted with 300 mL H2O, extracted with chloroform/methanol (95/5, 4×200 mL). The organic solution was concentrated to form methyl 4-bis(2'-hydroxyethyl)amino-3-(2'-(2"-methoxyethoxy)ethoxy)benzoate as an off-white oil (6.1 g, 92%). 1H NMR (300 MHz, CDCl3): 7.62 (dd, J=8.1, 2.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 4.22 (m, 4H), 3.89 (s, 3H, 3.9-3.8 (m, 4H), 3.68 (m, 6H), 3.58 (m, 2H), 3.38 (m, 2H), 3.37 (s, 1H). ESMS calcd (C17H27NO7): 357.2; found: 358.3 (M+H)+.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][N:17]([S:24](=[O:27])(=[O:26])[NH2:25])[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:6]1)(=O)C.C[O-].[Na+].CO.Cl>C1(C)C=CC=CC=1.O>[CH2:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([SH:4])[CH2:6][C@H:7]1[CH2:16][N:17]([S:24](=[O:26])(=[O:27])[NH2:25])[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methylpyrrolidine (6.70 g: 16.4 mmole) in toluene (50 ml), 4.92M solution of sodium methoxide in methanol (5.0 ml: 24.7 mmole) is added at -30° C. The mixture is stirred for 30 minutes, and diluted with water (55 ml). The aqueous layer is taken, diluted with toluene (50 ml), acidified with concentrated hydrochloric acid (2.3 ml) under ice cooling, and stirred. The organic layer is taken, successively washed with water and saturated brine, dried over magnesium sulfate and concentrated in vacuo. The residual oil is purified by silica gel chromatography (toluene-ethyl acetate) to give (2S,4S)-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methyl-4-mercaptopyrrolidine (4.89 g). Yield: 78%. Colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].C=O.Cl.[CH3:20]NC.C(O)(=O)C>C1C=CC=CC=1.CN(C=O)C>[CH2:20]=[C:12]([CH:13]([CH3:14])[CH3:15])[C:11]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:16]
Reactant: CNC
Reactant: COc1ccc(C(=O)CC(C)C)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C(C)C
Temperature: 0 °C

Procedure:
A stirred mixture of 2',3'-dichloro-4'-methoxyisovalerophenone (261.6 g., 1.0 mole), paraformaldehyde (75.0 g., 2.5 mole), dimethylamine hydrochloride (327 g., 4.0 mole) and acetic acid (26 ml.) is heated on a steam bath for 18 hours, treated with DMF (500 ml.), heated an additional three hours, then poured into ice water (1.7 l.). The crude product which separates is dissolved in benzene (600 ml.) and dried over sodium sulfate. Evaporation of the benzene affords 237 g. of 2-methylene-2',3'-dichloro-4'-methoxyiosovalerophenone which melts at 46°-51° C. and is used in Step C without further purification.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.N([O-])=O.[Na+].[ClH:17]>C(O)(=O)C.O.[Cu]>[Cl:17][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1
Reactant: Cl
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nnc(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 2-amino-5-phenyl-[1,3,4]thiadiazole (6.45 g, 36.4 mmol; Aldrich) and copper (230 mg, 3.6 mmol; Aldrich) in hydrochloric acid (36 mL, 12 M) and glacial acetic acid (180 mL) was chilled to 0° C. and treated with a solution of sodium nitrite (2.64 g, 38.2 mmol; Aldrich) in water (12 mL), added dropwise over 40 minutes. After stirring at room temperature for 4 hours, the mixture was poured into ice water. The aqueous solution was extracted with chloroform (3×), and the combined extracts were washed sequentially with 5% sodium bicarbonate and brine, and dried over sodium sulfate. The crude product was filtered through a short silica gel plug with chloroform to afford the title product: 1H NMR (300 MHz, CDCl3) δ ppm 7.46-7.55 (m, 3H), 7.85-7.93 (m, 2H) MS (DCI/NH3) m/e 197/199 (M+H)+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([OH:14])[CH2:8][C:7]1([CH3:16])[CH3:15].[OH-].[K+]>C1C=CC=CC=1>[C:1]([CH2:2][CH2:3][O:14][CH:9]1[CH2:8][C:7]([CH3:15])([CH3:16])[N:6]([CH3:5])[C:11]([CH3:13])([CH3:12])[CH2:10]1)#[N:4]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OCCC#N)CC1(C)C
Reaction time: 16 h

Procedure:
2.65 parts of acrylonitrile was added dropwise with stirring to a solution of 8.55 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol and 0.30 parts of 40% potassium hydroxide solution in 80 parts of benzene. Stirring was continued at room temperature for 16 hours after which time the solution was washed with water, dried and the benzene solvent removed by distillation under reduced pressure. Fractional distillation of the residue, under reduced pressure gave 1.70 parts of 4-(2'-cyanoethoxy)-1,2,2,6,6-pentamethylpiperidine having a boiling point of 105°-6° C. at 0.1 mm of Hg and the following elemental analysis by weight: