Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]1([F:26])[C@@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC(=O)OC2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>CN(C=O)C.CO>[C:1]([O:9][CH2:10][C@@:11]1([F:26])[O:12][C@H:13]2[N:18]3[CH:23]=[CH:22][C:21](=[O:24])[N:20]=[C:19]3[O:17][CH:14]2[C@@H:15]1[OH:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O)c1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OC[C@@]1(F)O[C@@H]2C(Oc3nc(=O)ccn32)[C@@H]1O)c1ccccc1
Temperature: 110 °C
Yield: 68 %

Procedure:
The benzyloxy protected 4′-fluorouridine (A3, 2.8 g, 7.6 mmol) was dissolved in DMF (10 mL). Solid diphenylcarbonate (1.80 g, 8.42 mmol, 1.1 eq) was added followed by solid sodium bicarbonate (0.36 g, 4.56 mmol 0.6 eq). The mixture was stirred and heated to 110° C. under an argon atmosphere for 8.5 hours at which time the reaction was shown to be complete by tlc (silica gel, EtOAc:MeOH=4:1). The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in methanol, and was purified by CombiFlash® column chromatography (Silica gel; 0 to 100% EtOAc:Heptane to 2:1 EtOAc:MeOH) providing the desired material in 68% yield (A4, 1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[C:6]([NH2:14])[CH:5]=1.[CH:16](O)=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][OH:13])[CH:16]=[N:14][C:6]=2[CH:5]=1)=[O:15]
Reactant: COC(=O)c1ccc(NCCO)c(N)c1
Reactant: O=CO
Product: COC(=O)c1ccc2c(c1)ncn2CCO
Temperature: 45 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
3-Amino-4-(2-hydroxy-ethylamino)-benzoic acid methyl ester (2.6 g, 12.0 mmol) was dissolved in formic acid (20 mL). The solution was heated at 45° C. for 1 h. After checking the completion of reaction by TLC, formic acid was evaporated at <40° C. under reduced pressure and the resulting solid was recrystallized from EtOAc. The above solid was dissolved in 3N HCl, stirred at ambient temperature for 1 h, basified back with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was evaporated to give 2.1 g (78%) of 1-(2-hydroxy-ethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 221 (M+1): 1H NMR (300 MHz, DMSO-d6) δ 3.7 (q, 2H), 3.9 (s, 3H), 4.3 (t, 3H), 5.0 (t, 1H), 7.7 (d, 1H), 7.9 (dd, 1H), 8.25 (s, 1H), 8.35 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:3]=1.[Cl:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1.N1C=CC=CC=1>>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=3)[N:3]=2)(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C#N)c1
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Yield: 85 %

Procedure:
To 3-{[3-amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 2) (7.89 g, 28.3 mmol) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (Aldrich) (6.15 g, 28.3 mmol) in pyridine (9.17 mL, 113 mmol) under nitrogen at room temperature. Reaction was exothermic and went deep red. After 40 minutes the reaction mixture was separated between ethyl acetate (500 mL) and 2N hydrochloric acid (500 mL). The aqueous phase was washed with ethyl acetate (400 mL). The combined organic solutions were dried over magnesium sulphate and evaporated in vacuo. The deep red residue was dissolved in DCM and applied to a 340 g silica cartridge. The cartridge was eluted with a gradient of 0-10% ethyl acetate in dichloromethane over 8CV. Evaporation of the appropriate fractions gave the title compound (11.1 g, 85%) as an off-white solid. LCMS (System A) RT=1.15 min, ES+ve m/z 459/461 (M+H)+.
Reaction SMILES: CO.CS(O)(=O)=O.C(OC([NH:18][CH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:39])[NH2:38])[CH:33]=3)[CH:28]=2)=[O:25])=[CH:22][CH:21]=1)=O)C1C=CC=CC=1.CS(O)(=O)=O.[H][H]>[Pd].CN(C=O)C>[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:38])[NH2:39])[CH:33]=3)[CH:28]=2)=[O:25])=[CH:40][CH:41]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)OCc4ccccc4)cc3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)cc3)ccc2c1
Reaction time: 3 h
Yield: 103.3 %

Procedure:
To a solvent mixture comprising 100 ml of methanol and 20 ml of DMF, were added 5.0 g 6-amidino-2-naphthyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, 1.0 g of 10% Pd-C and 1.1 g of methanesulfonic acid. Hydrogen was introduced into the mixture with vigorous stirring for 3 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to about half the volume. Ethyl ether was added to the concentrate and the precipitated crystals were collected by filtration to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl 4-aminomethylbenzoate dimethanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:5][CH:6]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:12]([C:9]1[S:8][C:7]([C:4]2[O:3][C:2]([CH3:1])=[CH:6][CH:5]=2)=[CH:11][CH:10]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)o1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)o1
Yield: 53.1 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methylisoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10% MeOH/CHCl3, gave 45 mg of the pure sulfonamide as a brown semisolid (54% yield, m.p. 123-124° C.).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[Br:31]Br>C(Cl)(Cl)Cl>[Br:31][C:8]1[O:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12

Procedure:
A solution of 4.0 g. (0.013 mole) of the product of step D in 50 ml. of dioxane is treated with 2.4 g. of bromine in 450 ml. of chloroform, and the mixture is heated at its reflux temperature overnight. The solution is cooled, washed with water, dried and then evaporated. The residue is triturated with hexane to provide 2-bromo-3,5-diphenylbenzofuran-7-carboxylic acid as a white solid, m.p. 232°-236° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:36][C@H:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:38][OH:39])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Intermediate 17 (0.25 g, 0.86 mmol), EDC (0.23 g, 1.2 mmol) and HOBT (0.139 g, 1.03 mmol) were suspended in DMF (5 ml) and the suspension was stirred at room temperature. After 25 min, (2R)-2-Amino-2-phenylethanol (0.13 g, 0.95 mmol, commercially available from Aldrich) was added, and the mixture was stirred at room temperature for 20 hours. Solvents were removed in vacuo and the residue was dissolved in DCM (50 ml) and washed successively with water (25 ml) and 5% sodium hydrogen carbonate solution (25 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and applied to a SPE cartridge (silica, 10 g), which was eluted with a gradient of ethyl acetate—petroleum ether (1:2, 1:1 and 1:0). Fractions containing the desired material were combined and concentrated in vacuo to afford Intermediate 42 as a white foam (0.318 g). LCMS showed MH+=410; TRET=2.55 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])#[N:2].[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24]>O1CCCC1.CCOCC>[C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][C:9]1([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])#[N:2]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)OCCC#N)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC1(CC(=O)OCCC#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The process is performed according to the procedure described in Example 18 (step 18.1.). Starting with 5.00 g (16.99 mmol) of tert-butyl 4-(cyanoethoxycarbonylmethylene)piperidine-1-carboxylate (WO 2006/001 752) in 56 mL of tetrahydrofuran, and 16.99 mL (33.97 mmol) of a 2M solution of isobutylmagnesium bromide in ether, 1.46 g of pure product are obtained in the form of a wax.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:5][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[N:6][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: Cc1ccccc1C(=N)N
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: Cc1ccccc1-c1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=358.9 (M+H+), was prepared from 2-methyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](Br)=[CH:12][N:13]=[C:7]2[C:6]=1[F:15])=[O:4].[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[C:27](B3OCC(C)(C)CO3)[CH:26]=[CH:25][C:24]=2[F:37])=[CH:21][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:27]3[CH:26]=[CH:25][C:24]([F:37])=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=4[C:38]#[N:39])[CH:28]=3)=[CH:12][N:13]=[C:7]2[C:6]=1[F:15])=[O:4]
Reactant: COC(=O)c1ccn2c(Br)cnc2c1F
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: COC(=O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 52.4 %

Procedure:
3-Bromo-8-fluoroimidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (0.10 g, 0.37 mmol) and 4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (0.15 g, 0.44 mmol) were coupled following the procedure in Example 1 to afford 3-(2′-cyano-2,4′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (79 mg, 53%) as a white solid: δH (400 MHz, CDCl3) 4.00 (3H, s), 7.35 (1H, dd, J 7 and 7), 7.34-7.46 (2H, m), 7.53-7.66 (4H, m), 7.85 (1H, s), 8.24 (1H, d, J 7); m/z (ES+) 408 (100%, [MH]+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[C:43]([O:51][C:52]([F:55])([F:54])[F:53])[CH:42]=1>CCOC(C)=O.C(Cl)Cl>[Br:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:7][CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:16]3[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:13][CH2:14]2)(=[O:49])=[O:48])=[C:43]([O:51][C:52]([F:55])([F:54])[F:53])[CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(N[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1nc(N[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid tert-butyl ester (500 mg, 1.25 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH2Cl2 (7 mL) was added diisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (446 mg, 1.31 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. To the reaction mixture was added a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (85 mg, 0.25 mmol) in CH2Cl2 (0.5 mL) and the mixture was stirred at 4° C. for 1 hr. To the reaction mixture was added diisopropylethylamine (220 μL, 1.26 mmol) and the mixture was stirred at 4° C. for 1 hr. The reaction was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide (624 mg, 83%) as a pale yellow solid.
Reaction SMILES: C([NH:8][CH:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH:16]1[C:13]2[CH2:14][CH2:15][CH:9]([NH2:8])[CH2:10][CH2:11][C:12]=2[CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CNC2CCc3ccccc3CC2)cc1
Agent: [Pd]
Solvent: CO
Product: NC1CCc2ccccc2CC1
Reaction time: 24 h

Procedure:
Benzyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine (2.80 g) is dissolved in methanol (100 mL) and the compound is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, dichloromethane/methanol 25:1 Rf=0.15).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13]C=1C(O)=O.CN(C=O)C>C(Cl)Cl>[F:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Oxalyl chloride (0.488 mL, 5.76 mmol) was added to a suspension of 2-fluoro-3-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DCM (10 mL) containing catalytic DMF. The reaction was stirred at room temperature for 90 minutes and solvents were removed in vacuo to afford the desired compound (1.08 g, 99%). The product was used without additional purification.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 2-methyl-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:21]=[C:20]4[C:19](=[CH:15][CH:14]=3)[N:18]([CH2:22][C:23]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc32)cc1

Procedure:
Example 124 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 4-methoxybenzylamine to give the title compound (0.011 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CN(C)[CH2:34][C:35]#[CH:36].CN([CH:41]=[O:42])C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:41][OH:42])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: C#CCN(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 125.6 mg (47%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])(O)=O.[Na+]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 7 h
Yield: 97.3 %

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (13.35 g, 0.0351 mol) was dissolved in 48% HBr (250 ml) and stirred at 105° C. (bath temperature) for 7 h. The mixture was poured on ice-water-brine and saturated aqueous NaHCO3 and extracted with AcOEt. The combined organic phases were washed with brine, dried over MgSO4, and evaporated in vacuo. The residue foam was treated with heptane over night. The precipitation was filtered and dried to give the title compound (12.5 g) as a white solid. MS (m/e, ISP neg. ion)=364.3 [M−H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)Nc1cccc(OC[C@@H]2CO2)c1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(NC(C)=O)c3)cc2)CC1
Yield: 28.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide 0.421 g, 1.0 mmol) was reacted with N-{3-[(2S)oxiranylmethoxy]phenyl}acetamide (0.207 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.168 g, 0.289 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:4][CH:3]=1.Cl.[O-:20][C:21]#[N:22].[Na+]>>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:17][CH:18]=1)[C:21]([NH2:22])=[O:20]
Reactant: N#C[O-]
Reactant: Nc1ccc(C=C2C(=O)Nc3ncccc32)cc1
Agent: Cl
Agent: [Na+]
Product: NC(=O)Nc1ccc(C=C2C(=O)Nc3ncccc32)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-aminobenzylidene)-7-azaoxindole (2.373 g, 10 mmol) in ice water (20 ml) are added 5N HCl (2 ml, 10 mmol under stirring. Then the mixture was heated to 70°-80° C., sodium cyanate (0.715 g, 11 mmol) was added portionwise and the stirring was continued for further 4 h at this temperature.
Reaction SMILES: [N+](=[C:3](P(=O)(OCC)OCC)C(=O)C)=[N-].[CH2:15]([C:17]1[N:18]([CH2:30][CH2:31][CH2:32][CH:33]=O)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:15]([C:17]1[N:18]([CH2:30][CH2:31][CH2:32][C:33]#[CH:3])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1)[CH3:16]
Reactant: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Reactant: CCc1nc2cnc3ccccc3c2n1CCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCCn1c(CC)nc2cnc3ccccc3c21
Yield: 80.1 %

Procedure:
Diethyl 1-diazo-2-oxopropylphosphonate (9.6 g, 1.2 eq.) was added to a solution of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal (11.15 g, 41.7 mmol, 1 eq.) and potassium carbonate (11.6 g, 2 eq.) in methanol. The reaction mixture was stirred until analysis by TLC indicated that all of the starting material had been consumed. The reaction mixture was filtered and the filter cake was rinsed until clear. The filtrate was concentrated under reduced pressure to provide crude product as an oil. The oil was partitioned between dichloromethane (200 mL) and water (100 mL). The organic layer was washed sequentially with water and brine (2×100 mL) and then concentrated under reduced pressure to provide 8.8 g of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinoline.