Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[OH:9])(=[O:3])[CH3:2].[Na].C(O)C.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][C:14]([CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[OH:9])=[O:3])=[O:18])[CH3:17]
Reactant: CC(=O)c1sccc1O
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1sccc1O
Reaction time: 15 h

Procedure:
4.8 g (0.0337 mol) of 2-acetyl-3-hydroxythiophene in 150 ml of diethyl carbonate are heated to 90°-100° C. 5 g of small sodium pieces are then added. Stirring is continued for 15 hours at 90°-100° C. To decompose remainders of sodium, a little ethanol is added. For working up, the mixture is extracted twice using 75 ml of water, the aqueous phase is then acidified with 10 ml of concentrated HCl, extracted 3 times with 50 ml portions of ether, dried, distilled in vacuo, and the fraction between 70° and 100° C. (0.6 mbar, educt) and between 113° and 118° C. (0.4 mbar product) is collected.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(Cl)Cl.[OH:33][CH:34]([CH2:39][CH3:40])[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>CCOCC>[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:33][CH:34]([C:35]([O:37][CH3:38])=[O:36])[CH2:39][CH3:40])=[O:24])=[CH:21][CH:20]=1
Reactant: CCC(O)C(=O)OC
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[N:3]=1.BrC1C=CC([N+:30]([O-:32])=[O:31])=CN=1>CN(C)C(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:30]([O-:32])=[O:31])=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#CC=C2CCN(c3ccc([N+](=O)[O-])cn3)CC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 59, but substituting NMP with N,N-dimethylacetamide and substituting 2-fluoropyridine with 2-bromo-5-nitropyridine. Purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with CHCl3-1.4 N MeOH NH3 100:0.5.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]([O:21][CH2:22][CH2:23][CH3:24])[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]([O:21][CH2:22][CH2:23][CH3:24])[CH3:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CCCOC(C)CCc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOC(C)CCc1ccc(-c2ccc(O)cc2)cc1
Yield: 101.5 %

Procedure:
2.6 g (8 mM) of the thus-obtained (-)-4-acetoxy-4'-(3-propoxybutyl)biphenyl was dissolved in 50 ml of methanol, added thereto with 10 ml of 20% NaOH aqueous solution, and then stirred at room temperature for 2 hrs. After completion of the reaction, the reaction mixture was made to pH 2-3 by adding 1N hydrochloric acid, and then further added thereto with 100 ml of ethyl acetate, and thereafter subjected to extraction treatment. The resulting organic layer was water-washed, and then concentrated under a reduced pressure to obtain 2.3 g of 4-hydroxy-4'-(3-propoxybutyl)biphenyl (V-47) with 100% yield
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1S(=O)(=O)Nc1c(C)nn(C)c1C
Yield: 93.3 %

Procedure:
Prepared from 4-bromo-2-methylbenzenesulfonyl chloride (0.736 g, 2.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) in pyridine (4.5 ml) according to the method of intermediate 1, to give the title compound as an orange solid (906 m, 2.52 mmol, 93%). δH (D-6 DMSO, 300K) 9.24 (1H, s), 7.70 (1H, d, J=1.5 Hz), 7.54 (1H, dd, J=8.5 Hz 1.5 Hz), 7.48 (1H, d 8.5 Hz), 3.55 (3H, s), 2.57 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES+, 70V) 360.0 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22])([CH3:17])[CH3:16].C[Al](C)C.CCCCCC>ClCCl>[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1nc2ccncc2s1
Reactant: CC(C)Oc1ccccc1CN
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1CNC(=O)c1nc2ccncc2s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (34 mg, 0.16 mmol) and 2-isopropoxy benzyl amine (67 mg, 0.41 mmol)in dichloromethane(1.7 mL) was added a solution of trimethylaluminum in hexane(0.203 mL, 2.0 M., 0.41 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 2:1) to give 30 mg of the thiazolo derivative.
Reaction SMILES: [CH3:1][C:2]1(C)[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:18]([OH:21])(=[O:20])[CH3:19].C(OC(=O)C)(=O)C.OS(O)(=O)=O>C(Cl)Cl>[C:18]([O:21][C@@H:4]1[CH2:9][C@@H:8]([C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[CH2:11][CH3:12])[O:7][CH:5]1[O:6][C:2](=[O:3])[CH3:1])(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CC[C@H](OC(C)=O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@@H](OC(C)=O)C(OC(C)=O)O1
Temperature: 22 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl]acetate (compound 6f, 4.8 g, 20 mmol), acetic acid (12.2 g, 200 mmol) and acetic anhydride (10.2 g, 100 mmol) in anhydrous DCM (100 mL) was added concentrated H2SO4 (0.5 mL) at 0° C. After being stirred at 22° C. for 3 hours, the reaction was quenched by addition of saturated NaHCO3 solution. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column on silica gel (eluting with 1:8 EtOAc in petroleum ether) to afford 2.3 g of [(3R,5S)-2-acetoxy-5-[(1S)-1-acetoxypropyl]tetrahydrofuran-3-yl] acetate (compound 6g) as a colourless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[O:14])[NH:11][CH:12]=1
Reactant: O=C(O)c1cc(I)c[nH]1
Reactant: Oc1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1Br)c1cc(I)c[nH]1
Temperature: 18 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Oxalyl chloride (203 mL, 2.32 mmol) was added to a magnetically stirred suspension of 4-iodopyrrole-2-carboxylic acid (8) (500 mg, 2.11 mmol) in dry CH2Cl2 (15.0 ml) containing dmf (1 drop). After stirring the resulting solution at 18° C. for 2 h it was added to a magnetically stirred solution of o-bromophenol (363 mg, 2.11 mmol), triethylamine (660 ml, 4.73 mmol) and 4-(N,N-dimethylamino)pyridine (dmap, several crystals) in CH2Cl2 (10 ml). After 1 h the reaction mixture was concentrated onto silica gel (5 g) and the residue subjected to flash chromatography (silica gel, 3:1 hexane/ether elution). Concentration of the appropriate fractions (Rf 0.2) then gave the title compound (761 mg, 92%) as a white crystalline solid, m.p. 126-127° C. (Found: C, 33.9; H, 1.7; Br, 20.4; I, 32.4; N, 4.0. C11H7BrINO2 requires C, 33.7; H, 1.8; Br, 20.4; I, 32.4; N, 3.6%). nmax (KBr) 3383, 2969, 1709, 1580, 1541, 1472, 1444, 1377, 1312, 1218, 1169, 1133, 1043 cm−1. 1H n.m.r. d 9.57, broad s, 1H; 7.65, dd, J 8.1 and 1.5 Hz, 1H; 7.37, td, J 8.1 and 1.5 Hz, 1H; 7.27, m, 2H; 7.18, td, J 8.1 and 1.5 Hz, 1H; 7.08, m, 1H. 13C n.m.r. d 158.0 (C), 148.3 (C), 134.0 (CH), 129.8 (CH), 129.1 (CH), 128.1 (CH), 124.4 (CH), 124.3 (CH), 123.6 (C), 116.9 (C), 62.9 (C). Mass spectrum m/z 393 (24%) 391 (22) (M+.); 220 (100) [(M−C6H4BrO)+.].
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3](O)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1>>[OH:1][CH:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:4]
Reactant: CC(O)C(=O)O
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)C(C)O)nc1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A8, starting from 2-hydroxy-propionic acid and 2-amino-5-picoline, 1H NMR (300 MHz, CD3OD) δ 8.11 (d, 1H), 8.05 (d, 1H), 7.64 (dd, 1H), 4.26 (q, 1H), 2.30 (s, 3H), 1.43 (d, 3H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1>C(Cl)Cl.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1)(=[O:3])[CH3:2]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(=O)OCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Acetic acid (2 ml) was added to a solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) in methylene chloride (10 ml). And to this solution was added silver acetate (0.34 g) under stirring at room temperature and then the mixture was stirred for 2.5 hours. After the reaction was completed, the reaction mixture was filtered under reduced pressure and the filtrate was washed with 5% hydrochloric acid and then filtered again. The oily residue was crystallized by treating with ether and the crystals were collected by filtration and then dried to give colorless needles of 2,2,2-trichloroethyl 2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.21 g), mp 116° to 118° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH2:32])=[N:27]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:32][C:28]2[CH:29]=[C:30]([CH3:31])[N:26]([CH3:25])[N:27]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)nn1C
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)nn1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of tert-butyl 5-[(2,5-dichloropyrimidin-4-yl)amino]-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (1.29 g, 3.46 mmol) and 1,5-dimethylpyrazol-3-amine (0.80 g, 7.20 mmol) in 1,4-dioxane (20 mL) was added trifluoroacetic acid (2.01 g, 17.60 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a yellow solid (294.5 mg, 19%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:28][CH2:29]C1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:28][CH2:29][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:21])=[O:22])[CH2:18][CH2:19]1
Reactant: COCCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COCCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(CO)cc23)CC1
Yield: 67.5 %

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 25) (30 mg, 0.065 mmol), [3-(hydroxymethyl)phenyl]boronic acid (40 mg, 0.26 mmols), cesium carbonate (42.5 mg, 0.13 mmol), and Pd(PPh3)4 (22 mg) in dioxane/water (2 mL/0.7 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (18.0 mg, 14%)
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>>[O:9]=[C:7]1[CH:2]2[CH:1]([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:10](=[O:11])[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: CC(C(=O)O)c1ccc(N)cc1
Product: CC(C(=O)O)c1ccc(N2C(=O)C3CCCCC3C2=O)cc1

Procedure:
Equimolar amounts of cyclohexane-1,2-dicarboxylic acid anhydride and α-(p-aminophenyl)propionic acid were treated as described in step (a) of Example 1, to yield quantitatively α-[4-(1,3-dioxo-hexahydro-2-isoindolinyl)phenyl]propionic acid, melting point 224°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12](O)=[O:13])[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([NH2:23])=[O:13])[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(C(N)=O)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
A suspension of 3.51 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1.78 g 1,1′-carbonyl-diimidazol in 30 ml DMF was stirred at room temperature for 18 hours. 0.8 ml Ammonium hydroxide (25% in water) was added and stirring was continued for 5 hours. Extraction with water/ethylacetate and crystallization from dichloromethane yielded 1.17 g (40%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide as a yellow solid; M.p.: 228–231° C.; MS (ISP): m/e=294 (M+H+). To a solution of 4.67 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide and 2.18 g imidazole in 95 ml pyridine were added at 0° C. 5.95 ml phosphoroxychloride. After 5 hours the cold solution was diluted with ethylacetate and extracted with water. The organic solution was dried with sodiumsulfate and the solvents were distilled off to yield 3.94 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonitrile as yellow solid; M.p.: 145–147° C.; MS (ISP): m/e=276 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O>[CH3:20][NH:21][C:22](=[O:23])[NH:1][CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Solvent: CN(C)C=O
Product: CNC(=O)NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
A suspension of 0.25 g of 9-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 0.49 g of 4-nitrophenyl N-methylcarbamate and 10 ml of dimethylformamide under an argon atmosphere is stirred for 4 hours at a temperature in the region of 20° C. The reaction mixture is filtered, washed successively with 5 ml of dimethylformamide and two times 20 ml of methyl-tert-butyl ether and then dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. 0.2 g of 9-[(3-methylureido)methyl]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a white solid, the melting point of which is greater than 260° C. (Analysis C16H15N5O2; % Calculated C: 62.13, H: 4.89, N: 22.64; % Found C: 62.03, H: 4.90, N: 22.26).
Reaction SMILES: [BrH:1].Br.[NH2:3][CH2:4][C:5]#[C:6][CH2:7][NH:8][C:9](=[NH:12])[CH2:10][F:11].N(CC#CCN[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[N+]=[N-].Br.C(SC(=N)CF)C1C=CC=CC=1>>[BrH:1].[CH2:24]([O:23][C:21]([NH:3][CH2:4][C:5]#[C:6][CH2:7][NH:8][C:9](=[NH:12])[CH2:10][F:11])=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOC(=O)NCC#CCN=[N+]=[N-]
Reactant: N=C(CF)NCC#CCN
Agent: Br
Agent: N=C(CF)SCc1ccccc1
Product: CCCCOC(=O)NCC#CCNC(=N)CF

Procedure:
1-Amino-4-(1-imino-2-fluoroethylamino)but-2-ynedihydrobromide was made from 1-azido-4-(butoxycarbonylamino)but-2-yne and S-benzyl-2-fluorothioacetimidate hydrobromide to yield 1-butoxycarbonylamino-4-(1-imino-2-fluoro-ethylamino) but-2-yne hydrobromide as an intermediate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[Br:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH2:27][N-:28][CH3:29])=[CH:20]2.C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH2:27][N:28]([CH3:29])[C:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=1)=[O:12])=[CH:20]2
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Reactant: C[N-]Cc1ccc2c(Br)c(OC)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(CN(C)C(=O)c3cn(C)c4ccccc34)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A solution of 1-methyl-1H-indole-3-carbonyl chloride (27 mmol), prepared in the previous step, in 50 mL of methylene chloride was added dropwise under nitrogen over 1.5 h to a solution of (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (7.56 g, 27 mmol), prepared in step 7 of Example 36, and triethylamine (3.76 mL, 27 mmol) in 200 mL of methylene chloride at room temperature. The solution was stirred at room temperature for 22 h (overnight). The reaction was extracted with 1N HCl. The aqueous layer was separated and extracted two additional times with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 11.52 g of an off white solid. The solid was recrystallized from methylene chloride-isopropanol. Off-white crystals were collected by filtration and dried under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (9.3389 g, 79%) as an off white solid, mp 168-169° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[OH:11].O[CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.CN1CCCC1=O>[Br:18][C:14]1[CH:13]=[C:12]([CH:10]([O:11][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1
Product: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
A mixture of 1H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9 g), 4-hydroxy-1-methylpiperidine (4.86 g) and para-toluenesulfonic acid (24 g) in chlorobenzene (60 mL) and N-methylpyrrolidone (6 mL) is heated under reflux for 120 h in a Dean Stark apparatus. Solvent is removed by evaporation. To the residue is added water which is made alcaline by addition of sodium hydroxide solution, then extracted with ethyl acetate. The pooled organic extracts are washed with water, treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated in diethyl ether to give 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([N:39]4[CH2:38][CH2:37][CH:36]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:41][CH2:40]4)=[CH:43][CH:44]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCOCC5)CC4)cc3)nn12
Yield: 21 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine (0.227 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and The reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 44.36 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=485.8. 1H NMR (400 MHz, DMSO, d6) δ 9.20 (s, 1H), 8.91 (s, 1H), 7.82 (dd, 1H, J=1.56, 6.16 Hz), 7.60 (d, 2H, J=9.01 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.17 Hz), 7.12 (t, 1H, J=7.28 Hz), 6.90 (m, 4H), 4.02 (m, 2H), 3.80 (s, 3H), 3.50 (m, 5H), 3.35 (m, 2H), 3.24 (m, 2H), 2.71 (m, 2H), 2.12 (m, 2H), 1.70 (m, 2H).