Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.S(Cl)([Cl:5])=O.[NH2:7][C:8]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:16]COCC>CC(C)=O>[ClH:5].[CH3:16][O:14][C:13]([C:8]1([NH2:7])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CCOCC
Reactant: NC1(C(=O)O)CCCC1
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C1(N)CCCC1
Product: Cl
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Preparation of methyl-1-N,N-dichloroamino-1-cyclopentanecarboxylate: To 30 ml of absolute methanol at 0° C, there was added dropwise with stirring over 0.5 hr. 7.9 ml of freshly distilled thionyl chloride. When the addition of thionyl chloride was completed, 12.9 g (0.1 mol) 1-amino-1-cyclopentanecarboxylic acid was added in portions over 0.25 hr. The suspension was heated with stirring, and the temperature maintained at 75° C for 2.5 hr. after solution of the reaction suspension. Removal of the methanol under reduced pressure gave an off-white crystalline mass. Trituration of this material with anhydrous ether gave 16.1 g (0.09 mol), 90%, methyl-1-amino-1-cyclopentanecarboxylate hydrochloride, mp 205°-207° C acetone:hexane, Kr (KBr) 1740 (C=O) cm-1 ; pmr (D2O) δ 3.95 (s, 3H) and 2.83 - 1.66 (m, 8H) ppm.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:21]1([CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:35]4[CH:36]=[N:37][NH:38][CH:39]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2nccn12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Product: c1cn2c(-c3cn[nH]c3)cnc(Nc3ccc(OCCN4CCOCC4)cc3)c2n1

Procedure:
In the same way as described for Compound 178, step 4 using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine (113 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (105 mg, 0.541 mmol), 1.5M Na2CO3 (1.44 mL, 2.14 mmol), and Pd(PPh3)4 (0.78 g, 0.67 mmol) in dioxane (4.3 mL). Purification by silica gel column chromatography eluting with 96:4 DCM:NH3 (7M in MeOH) followed by trituration with diethyl ether, affords the title compound as a free base (0.071 g, 65%). LCMS: Rt 1.59 min (100%), m/z (APCI) 406 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.40-2.60 (4H, m), 2.70-2.73 (2H, t), 3.61-3.63 (4H, m), 4.10 (2H, m), 6.94-6.97 (2H, d), 7.58 (1H, s), 7.74 (1H, s), 7.97 (2H, d), 8.06 (1H, s), 8.13 (1H, s), 8.41 (1H, s), 9.45 (1H, s), 13.41 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH3:21]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:25]2[N:24]=[N:23][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:26]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.0 mmol) in anhydrous THF at 0° C. may be treated with sodium hydride (60% dispersion in mineral oil) (1.3 mmol). After stirring for 15 min the reaction mixture is allowed to come to room temperature. To the alkoxide solution is added 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.74 mmol). After completion of the addition, the reaction mixture is warmed to 50° C. and is stirred 3 hours. The reaction is concentrated onto SiO2, purification via flash chromatography may be used (20-50% ethyl acetate in hexanes) to provide trans-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH3:3].[CH2:18]([O:20][C:21](=[O:29])[CH2:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1)[CH3:19].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:17][C:2]([CH3:1])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:28][C:25]2[S:26][CH:27]=[C:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:29])[N:24]=2)=[O:16])[N:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-[[1,1-Dimethylethoxy]carbonylamino]-4-thiazoleacetic acid (1.7 g) (Chem. Pharm. Bull. 1993, 41, 758), 2-amino-4-thiazoleacetic acid ethyl ester (1.35 g), 4-[dimethylamino]pyridine (0.8 g) and bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (3.3 g) in dry dichloromethane (50 ml) was treated with diisopropylethylamine (2.4 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with aqueous sodium bicarbonate and diluted with ethyl acetate. The organic solution was washed with brine and 2M HCl. The solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.8 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:21])[C:5](=O)[CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]2[S:14][C:15]([F:17])=[CH:16][C:12]=2[CH:11]=1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:17][C:15]1[S:14][C:13]2[CH:18]=[CH:19][C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]([CH3:21])[CH2:3][CH2:2][OH:1])=[CH:11][C:12]=2[CH:16]=1
Reactant: CN(CCO)C(=O)COCCc1ccc2sc(F)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(CCO)CCOCCc1ccc2sc(F)cc2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
In 7 mL of tetrahydrofuran is dissolved 0.70 g of N1-(2-hydroxyethyl)-N1-methyl-2-[2-(2-fluorobenzo[b]thiophen-5-yl)ethoxy]-acetamide. The solution is cooled to 5° C., to which is dropwise added 6.7 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran. The resulting mixture is stirred at ambient temperature overnight, 1.5 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for one hour. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 10.5 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 5:1) to obtain 0.58 g of 2-[{2-[2-(2-fluorobenzo[b]thiophen-5-yl)ethoxy]ethyl}(methyl)amino]-1-ethanol as an oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:16])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCC(=O)Cl
Temperature: 65 °C
Reaction time: 7 h

Procedure:
2,6-dimethylphenoxyacetylchloride is prepared in a separate vessel as follows: 2,6-dimethylphenoxyacetic acid, 5.4060 grams (29.99 mmol) is charged to a 50 mL round bottom flask equipped with a teflon-coated magnetic stir bar. Toluene, 15 mL is added stirring is initiated and thionyl chloride, 9.0 mL (123.3 mmol) is added followed by one drop of N,N-dimethylformamide at ambient temperature. After seven hours, the reaction mixture is heated to 65° C. for thirty minutes and allowed to cool to ambient temperature. The solution is concentrated at 60° C. and ca. 60 mm Hg pressure to remove all volatiles. The residue is diluted with toluene, 25 mL and reconcentrated. This is repeated a second time to give a final residue.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][CH:17]3[O:21]CC[O:18]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][C:17]([OH:21])=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C(CCC1OCCO1)c1ccccc1-2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1cccc2c1C(CCC(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
2-[2-(1-Methylfluoren-9-yl)ethyl]-1,3-dioxolane (4.8 g, 17.2 mmol) in 100 mL of acetone was charged slowly with John's reagent (CrO3 : H2SO4 :H2O 4:4:50 by weight) at room temperature. The reaction was monitored by TLC (silica, 10% ethyl acetate/hexane). The reaction mixture was stirred for 6 hr at room temperature, the acetone was evaporated and the residual water was extracted with ethyl acetate twice. The combined organic layers were washed with water until water became colorless. The organic solution was then extracted with 1N aqueous solution of sodium hydroxide. The basic aqueous solution was washed with ethyl acetate, acidified and extracted with ethyl acetate again. The ethyl acetate solution was dried over magnesium sulfate and evaporated. Purification of the crude by short path chromatography (silica, 25% ethyl acetate/hexane) afforded 2.6 g (59.9%) of 3-(1-methylfluoren-9-yl)propionic acid.
Reaction SMILES: O1CCC[CH2:2]1.[CH:6]([N-:9][CH:10](C)C)(C)C.[Li+].[C:14]([C:16]([C:30]#[N:31])=[C:17]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:18]1)#[N:15]>>[C:14]([C:16]([C:30]#[N:31])=[C:17]1[C:21](=[CH:6][N:9]([CH3:10])[CH3:2])[CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:18]1)#[N:15]
Reactant: C1CCOC1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(N2CCC(=C(C#N)C#N)C2)cc1
Agent: [Li+]
Product: COc1ccc(N2CC(=CN(C)C)C(=C(C#N)C#N)C2)cc1
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (7.1 mL, 10.5 mmol, in 1.5M in cyclohexanol) is added dropwise to a suspension of 3-dicyanomethylene-1-(4-methoxyphenyl)pyrrolidine (2.10 g, 8.8 mmol) in 150 mL of freshly distilled (over calcium hydride) tetrahydrofuran in a dry ice-acetone bath. After stirring for 1 hour, dimethylaminomethylene chloride (prepared from 1.64 mL of phosphorus oxychloride and 1.36 mL of N,N-dimethylformamide in 10 mL of tetrahydrofuran) is added dropwise, and the stirring is continued at -65° C. for 18 hours. The solid is collected by filtration and triturated with 50 mL of boiling ethanol to give 3-dicyanomethylene-4-(N,N-dimethylamino)methylene-1(4-methoxyphenyl)pyrrolidine (1.02 g, 40%), mp 218°-219° C. (decomposition), IR (KBr) 2210 cm-1 (CN), 1H NMR (Me2SO-d6) d 3.31 (6H, s, NMe2), 3.68 (3H, s, OMe), 4.23 (2H, brs, CH2), 4.44 (2H, brs, CH2), 6.60 and 6.85 (each 2H, d, Ph), 8.24 (1H, s, NCH=).
Reaction SMILES: S(Cl)(Cl)=O.CC(CCCC)C(O)=O.CC(CCCC)C(Cl)=O.[CH3:23][CH:24]([CH2:30][CH2:31][CH2:32][CH3:33])[C:25]([N:27]=[C:28]=[S:29])=[O:26].[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][C:43]1[C:52]2[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=2)[N:46]=[CH:45][CH:44]=1)[NH2:38]>C(O)C.C1(C)C=CC=CC=1>[Cl:34][C:35]1[CH:36]=[C:37]([NH:38][C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH2:30][CH2:31][CH2:32][CH3:33])=[S:29])[CH:39]=[CH:40][C:41]=1[O:42][C:43]1[C:52]2[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=2)[N:46]=[CH:45][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCCCC(C)C(=O)N=C=S
Agent: CCCCC(C)C(=O)Cl
Agent: CCCCC(C)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-methylhexanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-methylhexanoyl isothiocyanate was prepared using the resultant 2-methylhexanoyl chloride as a starting compound according to the description of the literature. 2-Methylhexanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2c(F)cccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 52.5 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.22 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 116 mg of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 123 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 0.15 g of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](C=O)=[CH:13][CH:12]=1)[CH3:2].CO[CH:22]([O:25][CH3:26])[O:23][CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:22]([O:23][CH3:24])[O:25][CH3:26])=[CH:15][CH:16]=1)[CH3:2]
Reactant: COC(OC)OC
Reactant: CCOC(=O)CCCCCOc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCOC(=O)CCCCCOc1ccc(C(OC)OC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3 (424 g, 1.60 mol), trimethylorthoformate (0.37 L, 3.40 mol) and p-toluenesulfonic acid monohydrate (15 g, 79 mmol) in MeOH (1 L) was stirred for 5 h at room temperature. Triethylamine (11 mL, 79 mmol) was added, the resulting solution was concentrated in vacuo, diluted with EtOAc (2 L) and subsequently washed with H2O (2×1 L) and saturated aqueous NaCl (1×1 L). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield an amber liquid (4, 481 g, 1.55 mol, 97%) with no need for further purification: 1H-NMR (400 MHz, CDCl3) δ=7.33 (d, J=8.7, 2H), 6.97 (d, J=8.7, 2H), 5.33 (s, 1H), 4.11 (q, J=7.1, 2H), 3.95 (t, J=6.4, 2H), 3.29 (s, 6H), 2.32 (t, J=7.4, 2H), 1.79 (m, 2H), 1.69 (m, 2H), 1.49 (m, 2H), 1.24 (t, J=7.1, 3H); 13C-NMR (400 MHz, CDCl3) δ=173.7, 159.3, 130.4, 128.0 (2C), 114.2 (2C), 103.2, 67.8, 60.4, 52.7 (2C), 34.4, 29.1, 25.8, 24.8, 14.4; IR(film) ν=2937, 1723, 1610, 1513, 1241, 1171, 1104, 1046, 980, 828 cm−1; HRMS (MALDI-FTMS) not detectable due to instability; detected: m/z 287.1254 (287.1252 calculated for parent aldehyde 3 C17H27O5Na, (M+Na)+).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13](=[O:15])[CH3:14])[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH4-].[Na+].O>CO>[OH:15][CH:13]([CH3:14])[CH:11]([N:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:2]1[CH3:1])[CH3:12]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(C)O
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To the solution of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (3.1 g, 10.25 mmol) in methanol (30 mL) was added sodium borohydride (0.30 g, 8.2 mmol) at 0° C. After 30 minutes, another batch of sodium borohydride (0.30 g, 8.2 mmol) was added at 0° C. After the reaction completed about 2 h later, water (30 ml) was added dropwise very carefully to quench the reaction. The mixture was extracted with CH2Cl2. The extraction was dried over Na2SO4, filtered and concentrated under vacuum to give tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a yellow solid. (3.0 g, yield 96%) LCMS (M+H+) m/z: calcd 305.38. found 304.9. 1H NMR (400 MHz, CDCl3): ii 8.31-8.29 (m, 1H), 8.13-8.12 (m, 1H), 7.11-7.07 (m, 1H), 4.46-4.43 (m, 1H), 4.12 (m, 1H), 2.73 (s, 3H), 1.58 (s, 9H), 1.51-1.49 (d, 3H), 0.92-0.91 (d, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=[C:2]2[C:22]1[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(Br)c2ccc(C)c(F)c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(C)c(F)c2n1
Temperature: 100 °C
Yield: 73.7 %

Procedure:
After degassing with N2, a mixture of methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 650 mg, 2.18 mmol.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (544 mg, 2.62 mmol) Pd(dppf)Cl2—CH2Cl2 adduct (89 mg, 0.11 mmol), and K3PO4 (1388 mg, 6.54 mmol) in 1,4-dioxane (12.9 mL) and H2O (1.6 mL) was heated at 100° C. for 20 min under microwave condition. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0-100%) to afford methyl 8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate (7-17, 481 mg, 74%). LRMS m/z (M+H)+ 300.3 found, 300.1 require.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([CH2:20][NH:17][C:15]2[S:16][C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:19]=[CH:18][C:13]=3[N:14]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1nc2ccc(OCCN3CCOCC3)cc2s1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2nc3ccc(OCCN4CCOCC4)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a round-bottom flask containing benzothiazole 226 (5.80 g, 20.8 mmol) was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol), followed by THF (8 mL), dibutyltin dichloride (315 mg, 1.04 mmol) and dropwise addition of phenylsilane (3.24 mL, 31.1 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The mixture was diluted in ethyl acetate and filtered. The filtrate was partitioned between ethyl acetate and water and the combined organic layers were washed with 1N HCl. The combined acidic layers were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was extracted with ethyl aceate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The resulting crude was purified by flash chromatography using MeOH/CHCl3 (10:90) to afford 227 (3.69 g, 42% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:31][C:32]([F:35])([F:34])[F:33])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:31][C:32]([F:35])([F:33])[F:34])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a solution of tert-butyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.103 mmol) and thioanisole (0.121 mL, 1.028 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.305 mL, 4.11 mmol). The solution was stirred at 23° C. for 3 h. The reaction mixture was concentrated. The residue was triturated with hexanes and purified by HPLC to provide the title compound as a white solid (19 mg). LCMS m/z=431.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.27-2.36 (m, 1H), 2.68 (dd, J=16.6, 8.2 Hz, 1H), 2.87-2.96 (m, 2H), 3.76 (quintet, J=7.5 Hz, 1H), 3.99-4.05 (m, 1H), 4.11-4.17 (m, 1H), 5.11 (s, 2H), 6.13 (s, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.43 (s, 1H), 7.57 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:12].Cl.[F:14][C:15]([F:31])([F:30])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])=[CH:19][CH:18]=1>C(O)C>[ClH:12].[NH2:25][C:24]1[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:15]([F:14])([F:30])[F:31])=[CH:22][CH:21]=2)[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[N:28]=[C:27]([NH2:29])[N:26]=1
Reactant: N=C(N)NC(=N)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(OC(F)(F)F)cc1

Procedure:
100 ml of ethanol, 4.7 ml (25.1 mmol) of 1-decanal and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.8 mmol) of N1-(4-trifluoromethoxyphenyl)-biguanide hydrochloride, and the mixture was refluxed for 16 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:1.5)), and recrystallized from 80% ethanol to obtain 1.1 g of colorless crystals having a melting point of 213 to 215° C.