Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1
Product: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 0.5 h

Procedure:
A solution of 4.0 g of N-[3-(1,6-dihydro-6-oxo-3-pyridazinyl)phenyl]acetamide in 100 ml of phosphorus oxychloride was heated at 55°-65° C. for 1.5 hours and then the excess phosphorus oxychloride was removed in vacuo. The residue was dissolved in dichloromethane and the solution poured onto 200 g of crushed ice. After stirring for 30 minutes the acidic mixture was neutralized with aqueous sodium bicarbonate. The mixture was filtered, giving 0.8 g of solid. The dichloromethane layer of the filtrate was separated, dried and evaporated, giving 2.93 g of solid. The two solids were combined (3.73 g) and a 2.9 g portion chromatographed on a silica gel column, eluting with dichloromethane-methanol (95:5). The fractions containing product were combined, evaporated and the solid (1.5 g) recrystallized from dichloromethane-acetone, to give the desired compound as tan crystals, mp 203°-205° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.[F:26][CH2:27][CH2:28][C:29](O)=[O:30].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.CC#N.O.O>[Br:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][F:26])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)CCF
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CCF)c23)C1
Reaction time: 1 h
Yield: 15.1 %

Procedure:
(R)-tert-Butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.280 g, 0.682 mmol; Example 98, Step A), 3-fluoropropanoic acid (0.314 g, 3.41 mmol), BOP-Cl (0.869 g, 3.41 mmol), and triethylamine (0.761 mL, 5.46 mmol) were placed in DCM (5 mL) and stirred for 1 hour. 3M aqueous LiOH (5 mL) was then added. The reaction was stirred for 1 hour, poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% CH3CN/water) to give (R)-tert-butyl 1-(5-bromo-3-(3-fluoropropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.050 g, 15% yield).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)[N:13]=1.[H-].[Na+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]>CN(C)C=O>[CH3:23][O:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:2]([O:1][CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])=[N:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N3CCOCC3)nc2n1
Yield: 11.5 %

Procedure:
The procedure is as in Example 26, but starting with 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (12.3 g) in dimethylformamide (150 cc), an oily suspension (50% by weight; 2.4 g) of sodium hydride and N-chloroacetylmorpholine (8.2 g). The residue obtained is purified initially by chromatography on silica (0.063-0.2 mm; 180 g) contained in a column 4 cm in diameter [eluant: methylene chloride/methanol mixture (95:5 by volume)], collecting 100-cc fractions. Fractions 190 to 210 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified again by flash chromatography on silica (0.040-0.063 mm; 82 g) contained in a column 3 cm in diameter (eluant: methylene chloride/methanol [98:2 by volume)], collecting 10-cc fractions. Fractions 220 to 235 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is recrystallized successively in acetonitrile and in ethanol. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-(2-morpholino-2-oxoethoxy)-1-isoindolinone (2 g), m.p. 192° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12](I)=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:7]=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12]([C:20]#[N:21])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-n1nc(C(F)(F)F)cc1I
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1-n1nc(C(F)(F)F)cc1C#N
Temperature: 200 °C
Yield: 106.3 %

Procedure:
To a stirred solution of 1-(5-chloro-2-methoxyphenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (4.83 g, 12.01 mmol, 1.0 eq) in NMP (20 mL) was added CuCN (1.03 g, 12.01 mmol, 1.0 eq) and the mixture heated to 200° C. for 2 h. The reaction mixture was passed through a celite pad and washed with excess of ethyl acetate. The filtrate was washed with water and the ethyl acetate layer was separated, dried (Na2SO4), and the solvent evaporated. The resulting residue was purified by CC using ethyl acetate/PE (1:19) to get 1-(5-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (3.85 g, crude, yellow solid; TLC system: EtOAc/PE (1:4) Rf: 0.65).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH:11]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C2C(=O)N(Cc3ccccc3)C(=O)C12
Solvent: C1CCOC1
Product: CCOC(=O)C1C2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 62.4 %

Procedure:
To a stirred solution of ethyl 3-benzyl-2,4-dioxo-3-aza bicyclo[3.1.0]hexane-6-carboxylate (SYNLETT, 1996, 1097; 5.0 grams, 18.3 mmol) in tetrahydrofuran (74 mL) cooled at 0° C., BH3-DMS (2N solution in tetrahydrofuran 36 mL, 73.2 mmol) was added over a period of 30 minutes. The reaction temperature was gradually raised to reflux for 6 hours. After cooling the reaction mixture to 0° C., it was quenched by adding aqueous ammonium chloride solution and was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain ethyl 3-benzyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (2.8 grams)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][S:9]([CH2:12][C:13]#[N:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]([S:19][CH2:20][CH2:21]OS(C(F)(F)F)(=O)=O)([F:18])[F:17]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][S:9]([CH:12]([CH2:21][CH2:20][S:19][C:16]([F:18])([F:17])[F:15])[C:13]#[N:14])(=[O:10])=[O:11])=[CH:4][CH:3]=1
Reactant: N#CCS(=O)(=O)Cc1ccc(Cl)nc1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1ccc(Cl)nc1

Procedure:
Compound II-7 was prepared from (6-chloro-pyridin-3-ylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[N:20][CH:21]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(N(CC)CC)C>[CH2:7]([C:6]1[CH2:16][CH2:21][CH:4]([C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:20]=[CH:21][C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][N:18]=3)=[CH:27][CH:26]=2)=[O:1])[CH2:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3CC=C(CCCCC)CC3)cc2)nc1
Reaction time: 1 h

Procedure:
2-{4'-[(4-pentyl-3-cyclohexenyl)-carbonyloxy]-phenyl}-5-decylpyrimidine is synthesized as follows. Tetrahydrofuran (35 carboxyl chloride (2.3 g) and 5-decyl-2-(4'-hydroxyphenyl)-pyrimidine (3.66 g). The reaction mixture is stirred until homogenous, then triethylamine (2.5 ml) is added. The reaction mixture immediately turns turbid. The turbid solution is stirred 1 hour, poured into a dilute (5%) hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers are then extracted with saturated sodium chloride, dried over sodium sulfate, and the solvent removed in vacuo. The product is purified by flash chromatography using 10% ethyl acetate in hexane as the eluent, and recrystallized from acetonitrile to produce the product, 2-{4'-[(4-pentyl-3-cyclohexenyl)-carbonyloxy]-phenyl)-5-decylpyrimidine.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][CH:16]([F:39])[C:17]1[N:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:18]=1[C:19]([NH:21][C:22]1[C:31]2[CH2:30][CH2:29][C:28]([CH3:33])([CH3:32])[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1)=O>O1CCOCC1>[F:15][CH:16]([F:39])[C:17]1[C:18]([C:19](=[S:2])[NH:21][C:22]2[C:31]3[CH2:30][CH2:29][C:28]([CH3:33])([CH3:32])[CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:34][C:35]([CH3:38])=[CH:36][N:37]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cnc(C(F)F)c(C(=O)Nc2cccc3c2CCC(C)(C)C3)c1
Solvent: C1COCCO1
Product: Cc1cnc(C(F)F)c(C(=S)Nc2cccc3c2CCC(C)(C)C3)c1
Yield: 91 %

Procedure:
In a microwave sealable tube, P2S5 (36 mg, 0.164 mmol, 0.5 eq) is added to a solution of 2-(difluoromethyl)-N-(6,6-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-methylnicotinamide (113 mg, 0.32 mmol, 1 eq) in 3 ml of dioxane. The tube is sealed and the reaction is microwaved 20 min at 130° C. The resulting solution is filtered through alumina and washed with dioxane. The solvent is evaporated and the residue purified by chromatography on silica gel to give pure material (91%)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)NC1CCC(O)c2sccc21
Reaction time: 8 h
Yield: 6 %

Procedure:
7-Keto-4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea (0.5 grams, 2.38 mm) is suspended in ethanol (50 ml.) and to the stirred solution is added solid sodium borohydride (0.5 grams, 13.2 mm). After stirring overnight the mixture is treated cautiously with 5% aqueous acetic acid (20 ml.). After stirring 15 minutes the solvent is removed, the residue dissolved in a small volume of methanol and percolated through a 11/2'×13/4" silica gel dry column eluting with 20% methanolic methylene chloride. The resulting gum is crystallized from ethyl acetate/methanol to afford 66 mg. (13% Y) of the more polar (L.L.C) alcohol (B), melting point 194° C. to 197° C. The mother liquor material is separated into its two major components 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea by high pressure liquid chromatography on "Spherosil XOA 400" using the solvent system: hexane (1800 ml.)/methanol (425)/chloroform (1000) (flow rate~13 ml./min.). This procedure affords the less polar alcohol A (29 mgs. 6% yield) melting point, 162° C. to 169° C. (methanol/ethyl acetate), and the more polar alcohol B (50 mg., 10% yield), melting point 197° C. to 198° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C(O[K])(C)(C)C.[CH3:18][O:19][C:20]1[C:25]([CH2:26][O:27][CH2:28][O:29][CH3:30])=[C:24]([C:31](=O)[CH2:32][CH3:33])[CH:23]=[C:22]([Si:35]([CH3:38])([CH3:37])[CH3:36])[N:21]=1.[Na+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[C:31](/[C:24]1[CH:23]=[C:22]([Si:35]([CH3:36])([CH3:37])[CH3:38])[N:21]=[C:20]([O:19][CH3:18])[C:25]=1[CH2:26][O:27][CH2:28][O:29][CH3:30])\[CH2:32][CH3:33]
Reactant: CCC(=O)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C\C(=O)OC)c1cc([Si](C)(C)C)nc(OC)c1COCOC

Procedure:
To a mixture of trimethyl phosphonoacetate (2.5 mL, 15.3 mmol) and tBuOK (1.7 g, 15.3 mmol) in THF (20 mL) at 0° C. (1 h) was added a THF (10 nmL) solution of 18 (1.2 g, 3.7 mmol). The mixture was stirred at reflux for 36 h. Purification of the crude residue by flash chromatography (hexane/EtOAc 92:8) followed by preparative HPLC (hexane/EtOAc 92:8, Novapak normal phase cartridge column, 10 mL/min), afforded in order of elution; 18 (123.3 mg, 10%), 19E (387.0 mg, 27%) and 19Z (609.3 mg, 43%) as clear oils: 19E; 1H NMR (300 MHz, CDCl3) δ0.28 (s, 9H), 0.99 (t, J=7.6 Hz, 3H), 2.99 (q, J=7.6 Hz, 2H), 3.42 (s, 3H), 3.75 (s, 3H), 4.02 (s, 3H), 4.47 (s, 2H), 4.72 (s, 2H), 5.8 (s, 1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−2.0, 12.3, 14.2, 26.6, 51.2, 53.4, 55.3, 61.9, 96.7, 115.4, 118.9, 121.1, 150.9, 160.3, 162.2, 164.9, 166.2; IR (film, NaCl, cm−1) 2949, 1723, 1341, 1042, 840; LRMS (70 eV, EI) m/z (rel int %) 367 (M+), 352, 322, 308 (100), 290, 276, 246, 232, 99, 57; HRMS m/z calcd for C18H29NO5Si (M+) 367.1815,m found 367.1802. 19Z: 1H NMR (300 MHz, CDCl3) δ0.26 (s, 9H), 1.11 (t, J=7.2 Hz, 3H), 2.38-2.48 (m, 2H), 3.4 (s, 3H), 3.53 (s, 3H), 3.99 (s, 3H), 4.35 (d, J=10.2 Hz, 1H), 4.51 (d, J=10.2 Hz, 1H), 4.66 (dd, J=6.3 and 14.2 Hz, 2H), 5.94 (s, 1H), 6.72 (s, 1H); 13C NMR (75 MHz, CDCl3 δ−1.9, 11.4, 33.1, 51.1, 53.2, 55.2, 61.9, 96.5, 114.5, 116.3, 120.6, 150.0, 159.0, 161.7, 164.3, 165.6; IR (film, NaCl, cm−1) 2941, 1732, 1559, 1457, 1342, 1054, 836; LRMS (70 eV, EI) m/z (rel int %) 367 (M+), 322, 290, 278, 262, 139 (100), 89, 73; HRMS m/z calcd for C18H29NO5Si (M+) 367.1815, found 367.1820.
Reaction SMILES: [Br-:1].ClC1C=CC=CC=1C(C1C=CC=CC=1Cl)(O)C(O[C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=O.[OH:38][C:39]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)[C:40]([OH:42])=[O:41]>>[Br-:1].[OH:38][C:39]([C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)([C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)[C:40]([O:42][C@@H:17]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:14][CH2:13]2)[CH2:16]1)=[O:41]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Reactant: COc1ccc(C(O)(C(=O)O)c2ccc(OC)cc2)cc1
Agent: [Br-]
Product: COc1ccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared analogously to (R)-3-[2,2-bis-(2-chloro-phenyl)-2-hydroxy-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1] by substituting bis-(2-chloro-phenyl)-hydroxy-acetic acid with hydroxy-bis-(4-methoxy-phenyl)-acetic acid (Intermediate C).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([OH:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][Cl:30].O>CC#N>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([O:12][CH2:28][CH2:29][Cl:30])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OCCCl
Yield: 50 %

Procedure:
The tert-butyl 3-amino-5-hydroxy-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate obtained above (12 g, 40 mmol) was dissolved in CH3CN (300 mL), followed by the addition of K2CO3 (11 g, 80 mmol) and 1-bromo-2-chloroethane (5.7 g, 40 mmol). The mixture was heated to reflux for 8 h, water (100 mL) was added and the mixture was extracted with ethyl acetate (60 mLx 3). The organic layers were washed with 0.5% aqueous sodium hydroxide (150 mL) and brine, dried over anhydrous Na2SO4 and then concentrated to give tert-butyl 3-amino-5-(2-chloroethoxy)-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate as a yellow solid (6.9 g, 50%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([C:37]1[N:38]=[C:39]([CH3:50])[N:40](COCC[Si](C)(C)C)[CH:41]=1)#[CH:36]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:8][C:4]1[CH:3]=[C:2]([C:36]#[C:35][C:37]2[N:38]=[C:39]([CH3:50])[NH:40][CH:41]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(Br)ccn1
Reactant: C#Cc1cn(COCC[Si](C)(C)C)c(C)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-2-methyl-pyridine (1.92 g, 11.2 mmol) was dissolved in 50 mL dry THF and triethylamine (3.9 mL, 30 mmol) was added. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphin (73 mg, 0.28 mmol) and bis(triphenylphosphin)palladium(II)chloride (327 mg, 0.47 mmol) were added and the reaction mixture was stirred at RT for 20 min. Copper(I)iodide (53 mg, 0.28 mmol) and a mixture of 4-ethynyl-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole and 5-ethynyl-2-methyl-1-(2-trimethyl-silanyl-ethoxymethyl)-1H-imidazole (2.2 g, 9.3 mmol) were added. The reaction mixture was then stirred at RT overnight. The solvent was evaporated. The residue was taken up in 50 mL water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 80:20 →0:100 gradient ) and the desired compound was obtained as a mixture of 2 isomers (2.86 g, 94%), MS: m/e=327.2 (M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)[N:3]=1.[CH2:25]([OH:27])[CH3:26]>>[CH:22]1([C:20]2[NH:19][N:18]=[C:17]([NH:16][C:4]3[N:3]=[C:2]([O:27][CH2:25][CH3:26])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[CH:21]=2)[CH2:24][CH2:23]1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1OC
Reactant: CCO
Product: CCOc1nc(Nc2cc(C3CC3)[nH]n2)cc2cc(OC)c(OC)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine and ethanol to give (5-Cyclopropyl-1H-pyrazol-3-yl)-(1-ethoxy-6,7-dimethoxy-isoquinolin-3-yl)-amine LC-MS m/e 355(MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([OH:28])=[CH:22][C:23](=[O:27])[O:24]3)=[CH:19][CH:18]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6].Cl>C(Cl)(Cl)Cl>[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([OH:28])=[C:22]([N+:1]([O-:4])=[O:2])[C:23](=[O:27])[O:24]3)=[CH:19][CH:18]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6]
Reactant: CCCc1c(OCC(O)COc2ccc3c(O)cc(=O)oc3c2)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCC(O)COc2ccc3c(O)c([N+](=O)[O-])c(=O)oc3c2)ccc(C(C)=O)c1O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Fuming nitric acid (9 ml) was added to a stirred suspension of 7-(3-[4-Acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxycoumarin (2.8 g) in chloroform (300 ml) over 1 hr at 0° and the dark mixture stirred for a further 0.5 hr at this temperature. Dilute hydrochloric acid (150 ml) was added and the chloroform removed in vacuo at 0°. The solid which separated was removed by filtration and recrystallised from ethanol to give 2.42 g, (78%) of yellow solid of mp 201°-203° (dec). νmax (mull) 3350 (br), 1770, 1620, 1610, 1540 cm-1 ; τ(DMSO); 9.17 (3H, t, J 6.9 Hz); 8.55 (2H, m, J ca 7 Hz); 7.43 (3H, S+2H, m); 5.78 (5H, S); 3.20 (3H, m); 2.16 (2H, exchangeable S); 2.16 (2H, near doublet); 1 low field broad exchangeable). (Found; C, 58.49; H, 5.07; N, 3.04; C23H23NO10 requires; C, 58.35; H, 4.90; N, 2.96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([C:20]1[S:21][C:22]([S:35][CH3:36])=[C:23]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([C:20]1[S:21][C:22]([S:35][CH3:36])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=3)[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cccc(B(O)O)c1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(N)c2)c1

Procedure:
Following the same procedure as in Example 1, step c, reaction of 3-amino-phenyl boronic acid (27 mg, 0.2 mmol), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (400 μL, 2M), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 35 mg (70%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white foam. ESI-MS (m/z): Calcd. for C23H25N3O4S3: 503.6; found: 503.9, 404.1 (M−Boc).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:26][O:25][N:24]([CH3:23])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Picolinic acid (12.3 g, 100 mmol), N,N-carbonyldiimidazole (17.8 g, 110 mmol) and anhydrous CH2Cl2 (150 mL) were combined and stirred at room temperature for 60 minutes. To the reaction mixture was added a solution of N,O-dimethylhydroxylamine hydrochloride (10.7 gr, 0.11 mole), anhydrous CH2Cl2 (50 mL) and diisopropylethylamine (20 mL), and stirring continued overnight. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, MeOH/CH2Cl2, 9:1) to afford pyridine-2-carboxylic acid methoxy-methyl-amide (a pale yellow liquid, 15.9 g, 95%); ESI) m/z 167.