Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[CH3:1][Si:2]([CH3:17])([CH3:18])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(CO)c1
Reactant: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2n1Cc1cccc(C)c1

Procedure:
This compound was prepared according to a process similar to that described in step 5.1 by reacting ethyl 6-trimethylsilyl-1H-indole-2-carboxylate prepared according to the process described in step 9.2 with (3-methylphenyl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by flash chromatography on a column of silica gel to give the expected product.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:23][N:22]=1>>[ClH:16].[CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][CH2:19][S:20][C:21]3[N:25]([CH3:26])[C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=4)=[N:23][N:22]=3)[CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cn1c(SCCCCl)nnc1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2cc3c(cc2o1)CCNCC3
Product: Cc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2ccc(C(F)(F)F)cc2)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.25 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole and was obtained as a faint yellow slightly hygroscopic solid (0.074 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:28][CH2:27]3)=[C:22]([C:23]#[N:24])[CH:25]=2)=[O:16])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1Cc1ccccc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1Cc1ccccc1
Yield: 22.9 %

Procedure:
The reaction and treatment in the same manner as in Example 64 were conducted using 1-benzyl-5-methylpyrazole-4-carboxylic acid (0.7 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.93 g) and the resulting product was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (0.36 g), melting point: 155° C.
Reaction SMILES: [NH3:1].[C:2]1([S:12](Cl)(=[O:14])=[O:13])[C:3]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1>C(O)C.C1(C)C=CC=CC=1>[S:12]1(=[O:14])(=[O:13])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:1]1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=S1(=O)NS(=O)(=O)c2ccccc21
Yield: 91 %

Procedure:
A solution of 0.65 mol of ammonia in 1,050 ml of absolute ethanol is added dropwise, with stirring, to 0.13 mol of 1,2-benzenedisulphonyl chloride in 720 ml of absolute toluene at 25° C. The mixture is stirred a further hour, slight cloudiness is removed by filtration through a layer of kieselguhr, and the filtrate is evaporated to dryness. The ammonium salt of 1,3,2-benzodithiazole 1,1,3,3-tetroxide is obtained.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Cl:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc([N+](=O)[O-])c1Cl
Yield: 80.5 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantanemethylamine (1.0 g) and 2-chloro-3-nitrobenzoic acid (1.22 g) to give the tidle compound as a yellow solid (1.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16]OC)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[NH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[NH2:23]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[ClH:21].[CH3:20][O:19][C:10]1[CH:11]=[C:12]([CH2:15][CH:16]=[N:23][NH:22][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccncc1
Reactant: COC=Cc1ccc(OCc2ccccc2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1cc(CC=NNc2ccncc2)ccc1OCc1ccccc1
Yield: 60.7 %

Procedure:
To a stirred solution of 1-benzyloxy-2-methoxy-4-(2-methoxyvinyl)benzene (11.0 g), 4-hydrazinopyridine hydrochloride (6.6 g), and ethanol (150 ml) was added p-toluene sulfonic acid (0.39 g). The reaction mixture was stirred under reflux for 2 hrs and concentrated in vacuo. Recrystallization of the residue from methanol/ether gave 9.48 g (61%) of product, mp 154-155° C.
Reaction SMILES: [CH2:1]([S:3]([CH:6]=[CH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])(=[O:5])=[O:4])[CH3:2]>Cl.CN(C)C=O.O.[Pd]>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 69.6 %

Procedure:
(R)-5-(2-Ethylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (157 mg) was dissolved in a mixture of ethanolic hydrogen chloride [prepared by addition of acetyl chloride (0.043 mL) to ethanol (10 mL)], N,N-dimethylformamide (7.5 mL) and water (0.1 mL) and the solution was shaken under a hydrogen atmosphere (15 psi) at room temperature for 18 hours in the presence of 10% palladium on carbon (150 mg). The mixture was filtered through Arbacel (trade mark) filter aid and the residue was washed well with ethanol. The combined filtrate and washings were evaporated under reduced pressure and the residual oil was partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic layer was separated, washed three times with water followed by brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a gum (110 mg): TLC (CH2Cl2 /C2H5OH/NH3 ; 90:10:1): Rf=0.3; [α]25D =+62° (methanol, c=0.10). Anal. Calcd for C18H26N2O2S. 0.05 CH2Cl2 : C,63.21; H,7.67; N,8.17. Found: C,63.55; H,7.61; N,8.41.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])[CH:4]=[C:3]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=1.C(#N)C.[CH3:22][N:23]([CH3:78])[C@H:24]1[CH2:75][C@@H:74]([CH3:76])[O:73][CH:26]([O:27][C@@H:28]2[C@@H:44]([CH3:45])[C:43](=[O:46])[C@@H:42]([CH3:47])[C:41](=[O:48])[O:40][C@H:39]([CH2:49][CH3:50])[C@:38]3([CH2:51][CH3:52])[C@H:34](N(CCCCN4C5C(=NC=CC=5)N=C4)[C:36](=[O:53])[O:37]3)[C@@H:33]([CH3:67])[C:32](=[O:68])[C@H:31]([CH3:69])[CH2:30][C@@:29]2([O:71][CH3:72])[CH3:70])[C@@H:25]1[OH:77]>O>[CH3:78][N:23]([CH3:22])[C@H:24]1[CH2:75][C@@H:74]([CH3:76])[O:73][CH:26]([O:27][C@@H:28]2[C@@H:44]([CH3:45])[C:43](=[O:46])[C@@H:42]([CH3:47])[C:41](=[O:48])[O:40][C@H:39]([CH2:49][CH3:50])[C@:38]3([CH2:51][CH3:52])[C@H:34]([N:11]([CH2:10][CH2:9][N:8]([CH2:7][C:5]4[CH:4]=[C:3]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[CH:2]=[N:1][CH:6]=4)[CH3:12])[C:36](=[O:53])[O:37]3)[C@@H:33]([CH3:67])[C:32](=[O:68])[C@H:31]([CH3:69])[CH2:30][C@@:29]2([O:71][CH3:72])[CH3:70])[C@@H:25]1[OH:77]
Reactant: CN(CCN)Cc1cncc(-c2cccnc2)c1
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc4ncccc43)C(=O)O[C@]12CC
Solvent: O
Solvent: CC#N
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCN(C)Cc3cncc(-c4cccnc4)c3)C(=O)O[C@]12CC
Yield: 27 %

Procedure:
C12 ethyl, C9, C10, C11 enone, 3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-[3,3′]Bipyridinyl-5-ylmethyl-N1-methyl-ethane-1,2-diamine (3 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{2-[(3,3′-bipyridin-5-ylmethyl)(methyl)amino]ethyl }-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (27% yield) as a white solid. MH+(852.50).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20](NC2C=C(C(O)=O)NC=2)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.[N+](C1C=C(C(O)=O)NC=1)([O-])=O.[F:48][C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[CH:51][C:50]=1[N+:58]([O-])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:58][C:50]2[CH:51]=[C:52]([CH:56]=[CH:57][C:49]=2[F:48])[C:53]([OH:55])=[O:54])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1c[nH]c(C(=O)O)c1
Agent: O=C(O)c1cc([N+](=O)[O-])c[nH]1
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cc(C(=O)O)ccc1F

Procedure:
Instead of the starting material compound of Example 262, that is, 4-nitropyrrole-2-carboxylic acid, 4-fluoro-3-nitrobenzoic acid was used for the similar procedure as in Example 262 to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[CH:10](O)=[O:11].CNC1(NC)C=CN=CC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[CH:10]([O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])=[O:11]
Reactant: O=CO
Reactant: C=CCOC(=O)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC1(NC)C=CN=CC1
Solvent: ClCCCl
Product: C=CCOC(=O)C(C)OC=O
Reaction time: 0.5 h
Yield: 54 %

Procedure:
5.00 g (41 mmol) of 2-propenyl 2-hydroxypropionate, 2.48 g (54 mmol) of formic acid, and 1.00 g (8 mmol) of 4,4-dimethylaminopyridine (nucleating agent) were dissolved in 30 g of 1,2-dichloroethane (solvent), and a mixed solution of 12.00 g (171 mmol) of N,N′-dicyclohexylcarbodiimide (dehydrating agent) and 20 g of 1,2-dichloroethane (solvent) was added thereto at 10° C., taking 30 minutes. These were reacted at room temperature for 3 hours, the reaction liquid was filtered to remove N,N′-dicyclohexylurea, and the filtrate was concentrated. The concentrate was purified through silica gel column chromatography, and from the fraction taken with hexane/ethyl acetate=8/1, 3.5 g (yield 54%) of 2-propenyl 2-(formyloxy)propionate was obtained.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[C:36]([C:38]1[S:42][C:41](S(N)(=O)=O)=[CH:40][CH:39]=1)#[CH:37]>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:41]3[S:42][C:38]([C:36]#[CH:37])=[CH:39][CH:40]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Reactant: NC(=O)N=S(=O)=O
Product: C#Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(-n3ccc4cc(N)c(F)cc4c3=O)cc2)s1

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-ethynylthiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-5-ethynylthiophene-2-sulfonamide. ES-MS (M+H)+=497.1; 1H-NMR (DMSO-d6) δ (ppm): 9.22-9.18 (bs, 1H), 7.70-7.66 (m, 1H), 7.65-7.60 (d, J=12.4 Hz, 1H), 7.48-7.42 (d, J=9.1 Hz, 2H), 7.40-7.36 (m, 1H), 7.32-7.25 (d, J=8.8 Hz, 2H), 7.24-7.18 (d, J=7.7 Hz, 1H), 6.72-6.66 (d, J=8.4 Hz, 1H), 6.58-6.48 (bs, 1H), 6.50-6.46 (d, J=7.3 Hz, 1H), 4.86-4.84 (s, 1H), 2.82-2.76 (s, 3H).
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C(=N)O[C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]1([C:5]([O:7][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)C1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 99 μl (0.78 mmol) of boron trifluoride/diethyl ether complex were added to 5.2 g (52.3 mmol) of cyclobutanecarboxylic acid in 100 ml of THF. A little at a time, 13.7 g (62.75 mmol) of tert-butyl 2,2,2-trichloroethaneimidoate were then added, and the mixture was subsequently stirred at room temperature overnight. 5 g of sodium bicarbonate were then added, and the reaction mixture was stirred for 15 min. After filtration, the solution was concentrated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 5.2 g (64% of theory) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])O[CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]>O>[CH3:1][N:2]1[C:8]([CH3:10])=[CH:9][C:4](=[O:3])[C:5]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6]1
Reactant: Cc1cc(=O)c(OCC(=O)O)co1
Reactant: CN
Solvent: O
Product: Cc1cc(=O)c(OCC(=O)O)cn1C
Reaction time: 3 h

Procedure:
To a stirred solution of 40% aqueous methylamine (9.0 ml) and water (9.0 ml) was added 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetic acid (6.0 g) in small portions at room temperature. The mixture was stirred at the same temperature for 3 hours and concentrated. To the residue was added water (5 ml) and the mixture was adjusted to pH 3. The resulting precipitates were collected and washed with water to give crystals of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid (1.53 g), mp 240° to 242° C. The filtrate and the washings were combined together and adsorbed on Amberlite IRA-400 (Tradename, prepared by Rohm and Haas Co.) and eluted with water and then 0.3 N hydrochloric acid. The hydrochloric acid fraction was concentrated and dried to give crystals (3.7 g) of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid hyrochloride. The hydrochloride was dissolved in a small amount of water and the solution was adjusted to pH 3. The resulting crystals were collected by filtration and washed with water to give an additional amount of the same product (2.2 g) as obtained above.
Reaction SMILES: C1(CCO)CC1.[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[OH:17])[CH2:14]2.FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41]>>[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[O:17][C:36]1[C:35]([Cl:34])=[CH:47][C:39]([C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41])=[C:38]([F:48])[CH:37]=1)[CH2:14]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1C2CC3CC(C2)CC1C3
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with adamantan-2-ol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.055 g, 4%): 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.33 (d, J=12.6 Hz, 1H), 4.82 (br s, 1H), 3.34 (s, 3H), 2.08-2.03 (m, 4H), 1.84 (br s, 6H), 1.71 (br s, 2H), 1.55-1.51 (m, 2H); MS (ES−) m/z 400.1, 402.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(C2=CCc3ccccc32)c1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC1C=C(c2cccc(OC)c2)c2ccccc21
Reaction time: 2.5 h
Yield: 19.8 %

Procedure:
To a cold solution of 3-(3-methoxyphenyl)indene (4 g, 18 mmol), prepared by the method of J. Med. Chem. 1981, 24, 998, in THF (15 mL) at 0° C. was added dropwise a solution of LiN(TMS)2 (20 mL, 1M in THF) over 5 min. The resulting solution was added dropwise to a solution of ethyl bromoacetate (3.34 g, 20 mmol) in THF (15 mL) at −78° C. over 30 min. After 2.5 h, the mixture was quenched with saturated ammonium chloride solution and the layers were separated. The organic layer was dried over MgSO4 and concentrated to give the crude product which was purified by column chromatography (SiO2/2-4% EtOAc/hexane) to give title compound (1.1 g): 1H NMR (400 MHz, CDCl3) δ1.30 (t, 3H), 2.50 (m, 1H), 2.85 (m, 1H), 3.85 (s, 3H), 4.0 (m, 1H), 4.20 (q, 2H), 6.6 (s, 1H), 6.9 (m, 1H), 7.2 (s, 1H), 7.35 (m, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26](Br)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Nc1ncnc(Br)c1C(=O)Nc1ccc(O)c(F)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3ccc(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.37 mmol), 4-amino-6-bromo-N-(3-fluoro-4-hydroxyphenyl)pyrimidine-5-carboxamide (183 mg, 0.56 mmol), DIEA (325 μl, 1.87 mmol) and cesium fluoride (113 mg, 0.74 mmol) were suspended in tert-butanol (5 ml) and the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 15 mg (8% yield) as a solid. Purity 99%.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH:54]1[CH2:59][CH2:58][CH:57]([CH2:60][C:61]([O:63]CC)=[O:62])[CH2:56][CH2:55]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([N:54]3[CH2:55][CH2:56][CH:57]([CH2:60][C:61]([OH:63])=[O:62])[CH2:58][CH2:59]3)=[O:35])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CCOC(=O)CC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CC1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a mixture of 20 mg of 3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid 4.1e, 28 mg of diisopropylethylamine, and 6.5 mg of ethyl 2-(piperidin-4-yl)acetate in 1 mL of DMF was added 17 mg of HATU. The mixture was stirred at 60° C. for 1 h. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, then brine. It was dried and the solvent was evaporated at reduced pressure. It was dissolved in 4:1 methanol/water and treated with 19.4 mg of LiOH.H2O. After stirring for 20 h the product was isolated by reverse phase HPLC, eluting with 0.5% TFA in a gradient of water and acetonitrile to give 10.9 mg of product. MS (ES, m/z): 728.7 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].IC.[OH-].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]cc([N+](=O)[O-])c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Reaction time: 16 h
Yield: 77 %

Procedure:
5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 mL) for 15 min. A solid formed. Iodomethane (5.3 mL, 85 mmol) was added and the flask was shaken until the solid dissolved. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 mL) was added, followed by water (100 mL). The solution was washed with ethyl acetate (100 mL), and the aqueous layer was acidified to pH 3 with 1.0N HCl. A precipitate formed as the pH was lowered. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washed with water, and air dried. The title compound was isolated in 77% yield as a yellow powder; m.p. 249 to 250° C.