Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[C:19]#[N:20].[OH:30][C:31]1[C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([N+:44]([O-:46])=[O:45])[CH:32]=1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C.O>[C:19]([C:18]1[C:17]([N+:22]([O-:24])=[O:23])=[CH:16][C:15]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:14]([CH:21]=1)[O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:30][C:31]1[C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([N+:44]([O-:46])=[O:45])[CH:32]=1)#[N:20]
Reactant: COCCOc1cc(C#N)c([N+](=O)[O-])cc1O
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOC
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a solution of 5-(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)-2-nitrobenzonitrile (0.2 g) in DMF (8 mL) was added 4-hydroxy-5-(2-methoxyethoxy)-2-nitrobenzonitrile (0.1 g) and K2CO3 (0.5 g). The resulting mixture was heated at 80° C. overnight under N2 atmospheres. After reaction finished, the mixture was diluted with water (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.2 g of 4-(2-(2-(2-(2-(5-cyano-2-(2-methoxyethoxy)-4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)-2-nitrobenzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 7.92 (s, 1H), 7.84 (s, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 4.35-4.25 (m, 8H), 3.95-3.89 (m, 4H), 3.85-3.78 (m, 4H), 3.77-3.63 (m, 8H), 3.45 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16]OC.C(OCC)(=O)C.Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[Cl:15][CH2:16][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N#Cc1ccccc1-c1ccccc1
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CCl)cc1
Yield: 48.3 %

Procedure:
To vigorously stirred 2-phenylbenzonitrile (68.1 g) under ice-cooling was added titanium tetrachloride (432 g) dropwise for 30 minutes. The precipitated crystals were pulverized and then chloromethyl-methyl ether (61 g) was added dropwise for 20 minutes with stirring under ice-cooling. After stirring at 60° C. for 2 hours, additional chloromethyl-methyl ether (15.3 g) was added and the mixture was stirred for an additional hour. To the reaction mixture was added ethyl acetate (200 ml) dropwise with stirring under ice-cooling. Then ice was added until hydrogen chloride gas development ceased and iced water (400 ml) was added before stirring for a while. The precipitated crystals were filtered and dried. The filtrate was extracted with ethyl acetate, washed with water, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography on silica gel to give crystals which were combined with the previously obtained crystal and recrystallized from methanol to yield pale yellow prisms (41.8 g, 48%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.CCCCCC>O>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH:36]2[CH2:35][CH2:34][N:33]([C:30]3[CH:29]=[CH:28][C:27]([S:24]([N:21]4[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]4)(=[O:26])=[O:25])=[CH:32][CH:31]=3)[CH2:38][CH2:37]2)=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CN1CCN(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1
Solvent: O
Solvent: CCCCCC
Product: CN1CCN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)CC1

Procedure:
The title compound was prepared from N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide, and 1-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-4-piperidinone in substantially the same manner, as described in Example 50. The product was obtained as a brown solid; mp: 89-91° C.; 1H NMR (400 MHz, DMSO-d6): δ 1.53-1.65 (m, 2H), 2.06-2.16 (m, 2H), 2.82-2.89 (m, 2H), 2.94 (s, 3H), 3.09-3.13 (m, 2H), 3.70 (brs, 2H), 4.01-4.05 (m, 2H), 4.76-4.79 (d, 2H), 6.11 (brs, 1H), 6.88-6.90 (d, 2H), 7.06-7.13 (m, 4H), 7.25 (s, 1H), 7.52-7.55 (d, 2H), 8.60 (brs, 1H); 8.58 (brs, 1H); 8.75 (s, 1H), 9.64 (brs, 1H), 10.00 (s, 1H); MS m/z 568 (M+H)+; Analysis for C25H37N5O6S2×0.4 hexane×0.52 H2O Calc'd: C, 42.07; H, 4.93; N, 7.34; Found: C, 42.27; H, 4.60; N, 6.70.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([C@H:25]([CH3:28])[CH2:26][CH3:27])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C@@H:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)[CH2:26][CH3:27]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Trichloromethyl chloroformate (5.4 g, 27.3 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-3-methylpentan-1-ol 13 (4.97 g of 60%, 11.1 mmol) and triethylamine (5.3 g, 52.0 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 3 h at 0° C., then allowed to warm to room temperature for 18 h. The mixture was then washed with HCl (3×100 ml) and water (2×100 ml) and dried over MgSO4. Concentration gave a crude product, which was washed with diethyl ether to afford the title compound 14 (2.7 g, 83%) as a white amorphous solid. m.p. 221–223° C. [α]D25=−243.9° (c, 4.33 in CHCl3). δH 0.41 (3H, t, J=7.2 Hz, CH3), 0.80 (3H, d, J=6.9 Hz, CH3), 0.80–0.96 (1H, m, CH2), 1.18–1.32 (1H, m, CH—Me), 1.34–1.50 (1H, m, CH2), 4.27 (1H, d, J=3.6 Hz, CH—NH), 6.98 (1H, s, NH), 7.10–7.50 (10H, m, Ar—H). δC 11.3 (CH3—CH2), 17.2 (CH3—CH), 22.7 (CH2), 36.3 (CH—Me), 66.1 (CH—NH), 89.5 (C), 125.9, 126.5, 127.7, 128.0, 128.3, 128.6, 139.3, 144.0 (Ar), 159.1 (C═O). νmax (cm−1): 3281, 3162 (N—H), 3058 (Ar C—H), 2980, 2960, 2933, 2877 (methyl and methylene C—H), 1760, 1725 (C═O), 1493, 1448 (Ar C═C), 1243 (C—O). m/e 313 (MNH4+, 6%), 296 (MH+, 8%), 237 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1cc(F)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-bromo-5-fluorophenol (15 g, 79 mmol) in 125 mL of anhydrous DMF was added K2CO3 (17.0 g, 138 mmol) and MeI (14.0 g, 102 mmol) under cooling, then the reaction was stirred at room temperature for 3 hours. The mixture was poured to water, extracted with diethyl ether, washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give 1-bromo-4-fluoro-2-methoxybenzene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][CH2:19]Cl.O>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:17][O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COCOc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,4-dihydroxybenzaldehyde (0.83 g) and cesium carbonate (1.7 g) in acetonitrile (30 mL) was added chloromethyl methyl ether (0.55 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gal (eluent: hexane/ethyl acetate=4/1) to give 2-hydroxy-4-(methoxymethyloxy)benzaldehyde (0.84 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH2:42])[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]>C1COCC1>[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH:42][C:11](=[O:13])[CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc4c(c3)CCO4)C2SC1
Temperature: 0 °C

Procedure:
A solution of 10 mmole of 2,3-dihydo-5-benzofuranyl acetic acid and 10 mmole of triethylamine in 100 ml of THF is cooled to about 0° C. While stirring, isobutylchloroformate (10 mmole) is added and the temperature maintained at 0° C. for 15 minutes. A cold solution of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (10 mmole) and 10 mmole of triethylamine in 80 ml of 50% aqueous THF is added to the previously prepared solution. The mixture is stirred at 5° C. for 1 hour and at room temperature for 1 hour. Then the THF is evaporated and the residue is dissolved in water and washed with ethyl acetate. The aqueous phase is covered with ethyl acetate and the pH is adjusted to 3 with 6N hydrochloric acid. The mixture is filtered and the layers separated. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Br:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cc(N)on1
Product: CCc1noc(N)c1Br

Procedure:
5-Amino-4-bromo-3-ethylisoxazole was prepared from 5-amino-3-ethylisoxazole and N-bromosuccinimide as described in Example 40a.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18]>>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][C:12]=1[F:18]
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: N#Cc1cccnc1F
Product: N#Cc1cccnc1Oc1cnc(Cl)c(F)c1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 6-chloro-5-fluoro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 250 (M)+, 252 (M+2)+.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:9]4[N:10]=[N:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: O=C(O)c1nnn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1nnn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 2-phenyl-2H-tetrazole-5-carboxylic acid (0.10 g, 0.53 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.15 g, 0.53 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.22 mL, 0.58 mmol, 1.1 eq) and HATU (0.22 g, 0.58 mmol, 3 eq). The mixture was stirred at room temperature for 1 h and was then concentrated and purified by HPLC to afford (S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-2-phenyl-2H-tetrazole-5-carboxamide (0.10 g, 0.26 mmol, 49%). 1H NMR (400 MHz, CD3OD) δ 8.19 (d, J=7.0 Hz, 2 H), 8.06 (s, 1 H), 7.95 (d, J=5.5 Hz, 1H), 7.82 (s, 1H), 7.70-7.58 (m, 3 H), 7.19 (d, J=5.8 Hz, 1 H), 5.00-4.90 (m, 1H), 4.80-3.80 (br, 4 H), 2.62-2.38 (m, 2 H); MS: (ES) m/z calculated for C18H17N9O [M+H]+ 376.2, found 376.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([N:30]2[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(CSc2ccccc2C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CSc2ccccc2C(=O)N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N1-(S-(4-methoxybenzyl)thiosalicyloyl)-N4-benzylpiperazine (compound 5) was prepared using the same procedure described above using: 10 mM(2.743 g) of S-(4-methoxybenzyl) thiosalicylic acid, 3 mM(728 mg) of 1-Benzylpiperazine and 20 mM (3.525 g)triethylamine. The product was dissolved in 5 ml of methylene chloride and purified by column chromatography on a silica gel column (eluent: Ethyl acetate) to give 870 mg(20.1%) of a white crystal. The product was then further purified by crystallization from hexane. The purified product had having a melting point of 84-85° C. and had the following specifications:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)[CH:16]=5)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(CCOS(C)(=O)=O)cc3-5)cc2Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(CCN4CCN(C)CC4)cc3-5)cc2Cl)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To 4 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethyl methanesulfonate (100 mg, 0.17 mmol), 1-methylpiperazine (0.06 mL, 0.5 mmol), and diisopropylethylamine (0.06 mL, 0.33 mmol). The mixture was stirred at 70° C. for 16 h after which time the mixture was removed from heating, and allowed to cool to rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (43 mg, 43%) as a white solid. 1H-NMR (DMSO-d6) δ 8.43 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.73 (d, 1H), 7.51 (dd, 1H), 7.35 (d, 1H), 7.22 (s, 1H), 7.19 (s, 1H), 5.22 (s, 2H), 4.17 (t, 2H), 3.38 (t, 2H), 2.91 (t, 2H), 2.70 (t, 2H), 2.48 (s, 3H), 2.40-2.48 (br s, 4H), 2.25-2.35 (br s, 4H), 2.13 (s, 3H); LCMS RT=2.07-2.24 min, [M+H]+=601.4.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:6][C@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C@@H:3]([CH:2]=[O:1])[CH2:4]1
Reactant: OC[C@H]1CNC[C@@H]1c1ccsc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.4 g (13.1 mmol) of 3-(R)-hydroxymethyl-4-(S)-(3-thienyl)pyrrolidine, 6.8 mL (39 mmol) of diisopropylethylamine, and 4.1 g (23.4 mmol) of 2,4-dichlorobenzaldehyde (Aldrich) in 60 mL of CH2Cl2 at rt was added 5.5 g (26 mmol) of sodium triacetoxyborohydride in several small portions and the reaction mixture was stirred at rt for 3 h. To the reaction was added 50 mL of sat'd NaHCO3 solution and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:acetone, 4:1) to give the title compound. Mass Spectrum (ESI) m/e=342 (M+1 35Cl, 35Cl), 344 (M+1 35Cl, 37Cl), and 346 (M+1 37Cl, 37Cl). 1H-NMR (CDCl3, 500 MHz): 7.38 (m, 2H), 7.30 (m, 1H), 7.23 (m, 1H), 7.03 (m, 2H), 3.65-3.77 (m, 3H), 3.34 (m, 1H), 3.21 (t, J=8.5 Hz, 1H), 2.82 (m, 2H), 2.70 (m, 1H), 2.52 (t, J=8 Hz, 1H), 2.38 (m, 1H). 13C-NMR (CDCl3, 125 MHz): 145.0, 134.7, 134.6, 133.3, 131.3, 129.3, 127.0, 126.9, 126.0, 119.8, 66.2, 61.7, 57.8, 56.1, 48.0, 41.7.). [α]D=+3.0 (c=1.75, CHCl3).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[N:6]1[CH:5]=[C:4]([NH:3][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:9]=[N:8][CH:7]=1
Reactant: Nc1cncnc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5cncnc5)nc34)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 5-aminopyrimidine (AK Scientific, Union City, Calif.; 0.168 g, 1.76 mmol). After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. After 2 h, the reaction was cooled to 0° C. and TFA (0.136 ml, 1.763 mmol) was added along with 1 mL DMSO. The reaction was filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-60% ACN/H2O with 0.1% TFA); the product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM and 1× EtOAc. The combined organic layers were then treated with MeOH until the solid dissolved, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 2-(2-(pyrimidin-5-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.039 g, 0.109 mmol, 43% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (1H, br. s), 9.84 (1H, s), 9.21 (2H, s), 8.82 (1H, s), 8.21 (1H, d, J=8.8 Hz), 7.83 (1H, dd, J=7.2, 1.6 Hz), 7.70 (1H, dd, J=8.0, 1.6 Hz), 7.37 (1H, t, J=7.6 Hz), 7.15 (1H, d, J=8.8 Hz), 6.82-6.95 (1H, m), 6.66 (1H, d, J=2.2 Hz), 3.37-3.54 (2H, m), 2.83 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 357.0 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5](/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:6][P:7](=[O:12])([O:10]C)[O:8]C)(=[O:3])[CH3:2].N1C(C)=CC(C)=CC=1C.C[Si](Br)(C)C>ClCCl.C1(C)C=CC=CC=1.[OH-].[NH4+]>[C:1]([NH:4][CH:5](/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:6][P:7](=[O:8])([OH:10])[OH:12])(=[O:3])[CH3:2]
Reactant: COP(=O)(CC(/C=C(\C)CC/C=C(\C)CCC=C(C)C)NC(C)=O)OC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Product: CC(=O)NC(/C=C(\C)CC/C=C(\C)CCC=C(C)C)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl [2-acetamido-(E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]phosphonate (39 mg, 0.101 mmol) and 2,4,6-collidine (0.054 ml, 0.404 mmol) in dichloromethane (2.5 ml) under argon at 0° C., was added trimethylsilyl bromide (0.054 ml, 0.404 mmol) and the resulting mixture stirred at 0° C. for 30 min and then at r.t. for 5 hr. The resulting white suspension was diluted with toluene (10 ml) and the solvent evaporated in vacuo. The resulting white solide was dissolved in ethylacetate and water and the pH was adjusted to 3 by the addition of 1M HCl solution. The organic layer was separated, dried (Na2SO4) and evaporated to afford a clear oil, which was dissolved in hexanes and treated with 10 drops of ammonium hydroxide, the precipitate was removed by filtration and dried in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]#[N:29])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)SC)#[N:2].[NH3:30].CO>N.C(O)(C)C>[C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]#[N:29])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)[NH2:30])#[N:2]
Reactant: N
Reactant: CSC(=NC#N)N1CCC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Solvent: CO
Solvent: CC(C)O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CCN(C(N)=NC#N)CC1
Temperature: 100 °C
Reaction time: 0.1 h

Procedure:
Methyl N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-piperidine-1-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100° C. for 1 h in a microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 375 (50 area %). To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was heated at 120° C. for one hour. HPLC and LCMS analyses showed no remaining starting material. The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep HPLCMS using a 30 mm×100 mm C18 column, eluting with a solvent gradient; 10% ACN—H2O (0.1% TFA), 1.5 min, to 30% at 6 min; 60 mL/min; detector set at m/z 375; retention time, 4.7 min. The eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 1H NMR (d6-DMSO) δ 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS (ES) 375 (M+H).