Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:27]=[CH:26][C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:24][C:18]=1[O:19][CH2:20][C:21](O)=[O:22])[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)[C:42]([O:44][CH2:45]C)=[O:43].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C>[CH2:1]([N:8]([CH2:16][C:17]1[CH:27]=[CH:26][C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:24][C:18]=1[O:19][CH2:20][C:21]([NH:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)[C:42]([O:44][CH3:45])=[O:43])=[O:22])[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)O
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)Nc1cccc(C(=O)OC)c1
Reaction time: 5 h

Procedure:
A room temperature solution of Example 21A (50 mg, 0.10 mmol) in DMF (1.0 mL) was treated with ethyl 3-aminobenzoate (20 μL, 0.13 mmol), HOBT (23 mg, 0.14 mmol), EDCI (29 mg, 0.15 mmol), and Et3N (21 μL, 0.15 mmol), stirred for 5 hours, and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:5 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: O=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]2)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:20][NH2:21]>CN(C)C=O>[O:6]=[C:5]1[CH2:4][CH2:3][C:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)=[N:21][NH:20]1
Reactant: NN
Reactant: CN1C(=O)Cc2cc(C(=O)CCC(=O)O)ccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)Cc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
A solution of 7 g of 4-oxo-4-(1-methyl-2-oxoindolin-5-yl)butanoic acid and 3 ml of hydrazine hydrate in 70 ml of dimethylformamide was heated on a water bath for 4 hours. The precipitated crystals were filtered off and recrystallized from dimethylformamide to give 4.0 g of 5-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methylindolin-2-one as pale yellow prisms, melting at 261°-264° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=O.[NH3:29]>>[F:26][C:24]([F:25])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:29]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2C(F)(F)F)c1C
Reactant: N
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3C(F)(F)F)nc2c1C
Yield: 15 %

Procedure:
Instead of the compound of formula (II) used in Example 1, ethyl 4-formyl-2,6-dimethyl-3-(o-trifluoromethylbenzoylamino)benzoate was used and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column. The solvent was evaporated, and the residue was recrystallized from ethanol to give 2-(o-trifluoromethylphenyl)-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 68° to 69° C. in a yield of 15%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: CCOC(=O)c1cc(OCc2cccc([N+](=O)[O-])c2)cc(Oc2ccc(C#N)cc2)c1
Yield: 80.8 %

Procedure:
Using 1.2 g (4.23 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and 1-bromomethyl-3-nitro-benzene (0.913 g, 4.23 mmol) and following the procedure of Example 42(b) afforded 1.43 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 5.4 (2H, s), 7.2 (4H, m), 7.45 (1H, s), 7.72 (1H, t), 7.9 (3H, m), 8.25 (1H, d), 8.35 (1H, s).
Reaction SMILES: [NH2:1][S:2]([CH:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])(=[O:4])=[O:3].Cl>C(O)C.[Pd]>[NH2:1][S:2]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])(=[O:3])=[O:4]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(N)(=O)=O)cc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(N)(=O)=O)cc12
Yield: 49.8 %

Procedure:
(R)-5-(2-Aminosulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (157 mg, 0.5 mmol) was dissolved in absolute ethanol (10 mL) and added to a solution of ethanolic hydrogen chloride (25 ml) (prepared from acetyl chloride (38 μL, 0.53 mmol) and absolute ethanol (25 mL)). 10% palladium-on-carbon (125 mg) was added. This solution was hydrogenated under a hydrogen atmosphere (15 p.s.i.) at room temperature for 18 hours. The resultant reaction mixture was filtered through diatomaceous earth (Celite trademark or Arbacell-trademark)) washed with absolute ethanol and the combined filtrates evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient solvent mixture up to CH2Cl2 : MeOH:NH4OH 93:7:1 to give the title compound as a colourless oil (80 mg, 51%). Anal. Calcd for C16H23N3O2S·1/4 MeOH. 1/3 H2O: C,58.21; H,7.36; N,12.54. Found: C,58.60; H,7.40; N,12.57. [α]25D =+69° (c=0.1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27]C[CH:25]([NH2:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:25]([NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[C:18](=[O:43])[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=2[CH3:41])[C@@H:26]([OH:30])[CH2:27][CH2:28][CH3:29])[C:21]1=[O:42])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=1[C:18]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=2[CH3:41])[C@@H:26]([OH:30])[CH2:27][CH2:28][CH3:29])[C:21]1=[O:42])=[O:43]
Reactant: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2N)C1=O
Yield: 66.2 %

Procedure:
The compound {2-[(3S)-1-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2-oxo-pyrrolidin-3-ylcarbamoyl]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (9 mg) was dissolved in 3 mL of 2:1 CH2Cl2/TFA. The resultant solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in TFA and concentrated in vacuo; this procedure was repeated. Lyopholization (H2O/MeCN) afforded the title compound as a white powder (5 mg). MS found: (M+H)+=521.5.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=O)(OCC)OCC)#N.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reactant: Oc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 8 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.543 g), 0.245 g of phenol, 0.48 ml of triethylamine, and 6 ml of dichloromethane are added 0.42 ml of diethyl cyanophosphonate. After stirring for 1 hr an additional 0.11 g of phenol are added. When the reaction had stirred another 2.5 hr an additional 0.11 g of phenol and 0.26 ml of diethyl cyanophosphonate are added. The reaction is stored overnight in the refrigerator and then stirred with 1 ml of aqueous sodium bicarbonate for about 30 min. The mixture is then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel (300 ml) elating with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, which is crystallized from dichloromethane/hexane, mp 196.5°-199°; MS (m/z) at 388; IR (mineral oil) 1648, 1199, 1723, 1502, 1410 cm-1 ; 1H NMR (CDCl3) 1.81, 3.31, 5.09, 7.15-7.33, 7.42, 7.55, 8.11 δ.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:25])[CH3:24]>COC(C)(C)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:25][CH2:23][CH3:24])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CCN
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC#CCOc1cc(NCC)ncn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 20 ml of dimethylsulfoxide were added 1.83 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 2.20 g of potassium carbonate, and 20 ml of ethylamine (2.0 M tetrahydrofuran solution), followed by stirring at 50° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with tert-butyl methyl ether, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from tert-butyl methyl ether to give 1.14 g of 4-(2-butynyloxy)-6-(ethylamino)pyrimidine (the present compound (108)).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)(C)(C)C.[ClH:25]>CCOCC.O1CCOCC1>[ClH:25].[NH2:7][CH2:8][C:9]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14]1
Reactant: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N1CCC(CN)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1-acetyl-4-phenylpiperidin-4-ylmethyl)carbamic acid tert-butyl ester in ether is added 4 N HCl in 1,4-dioxane. The reaction mixture is stirred at room temperature for 1 h, and concentrated in vacuo. The resulting solid is washed with ether to give the title compound, which is directly used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([NH2:17])=O)[CH2:6][C:5]2=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15][NH2:17])[CH2:6][C:5]2=1
Reactant: NC(=O)C1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 0 °C
Yield: 52 %

Procedure:
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide (0.6 g, 2.42 mmole) was dissolved in THF (20 ml). The reaction was cooled to 0° C. Lithium aluminum hydride (4.8 ml, 1M, 4.8 mmole) was portion wise carefully added. The reaction was refluxed for 2 hours. After cooling the mixture to room temperature water was carefully drop wise added to deactivate the Li—Al-complex. The formed solids were filtered and the filtrate diluted with ethyl acetate, washed with water (2×), brine and the separated organic layer dried over magnesium sulfate, filtered and evaporated in vacuo. The product was crystallized from ethyl acetate/hexane, 80:20. A white solid was obtained, 0.293 g, 52% yield. mp. 142-144° C. MS: ES [M−H]− 233.1.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:21]([N:40]1[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[CH:58]=[CH:57][C:54]([CH2:55]Br)=[CH:53][CH:52]=2)=[N:43][N:42]=[N:41]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[C:44]3[N:40]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:41]=[N:42][N:43]=3)=[CH:58][CH:57]=2)[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 18(a), but using 0.26 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 8), 45.5 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 0.63 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.2 8 g of the title compound were obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]([C:14]([OH:16])=O)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([C:14]([Cl:19])=[O:16])=[C:11]=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(C(C(=O)O)C(=O)O)cc1C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=C=O)C(=O)Cl)cc1C
Temperature: 95 °C

Procedure:
30 g of 2-(2,4,5-trimethylphenyl)-malonic acid were suspended in 60 ml of toluene at 50 to 60° C. and 62.5 ml of thionyl chloride-were added dropwise. The mixture was then heated at 90 to 100° C. for 15 hours. It was then cooled, the volatile constituents were driven off with an inert gas and the excess thionyl chloride was distilled off. 30.6 g of 2,4,5-trimethylphenylchlorocarbonyl ketene were isolated as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][C:18]([O:20]CC)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24]
Reactant: CCOC(=O)C=CC=CC=CC=Cc1c(C)cc(OC)c(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C)c(C=CC=CC=CC=CC(=O)O)c(C)c1C
Reaction time: 18 h
Yield: 14.1 %

Procedure:
A solution of 6.1 g (0.019 mol) of the ethyl ester of Example 1 was dissolved in 15 mL of ethanol and a solution of KOH (1.6 g, 0.028 mol) in 5 mL of ethanol and 1 mL of water was added. The mixture was stirred under nitrogen for 18 hrs and ethanol was evaporated in vacuo. The residue was dissolved in 100 mL of water and the resulting mixture extracted with three 20 mL-portions of ethyl acetate. The organic layers were discarded. The aqueous layer was cooled in an ice bath and acidified to pH 3 with 10N hydrochloric acid. The yellow precipitate was extracted into ethyl acetate, washed with brine and dried. Evaporation of solvent in vacuo afforded a yellow substance. Crystallization from ether gave 0.8 g of the product as yellow crystals: mp 187°-189° C.; MS-298 (m+); UV(MeOH) λmax 340 nm.
Reaction SMILES: [CH3:1][CH:2]1[CH:7](C(OCCCC)=O)[C:6](=O)[CH2:5][C:4](=[O:16])[CH2:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CS(C)=O>[CH3:1][CH:2]1[CH2:3][C:4](=[O:16])[C:5]2[S:24][C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:17][C:6]=2[CH2:7]1
Reactant: Nc1ccccc1S
Reactant: CCCCOC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: CC1CC(=O)C2=C(C1)Nc1ccccc1S2

Procedure:
A mixture of ter butyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7c (3.09 g, 13.7 mmole) and 2-aminothiophenol, 6 (X=H, 1.71 g, 13.7 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate was separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4d, (R=H), mp 278° C. occurs as light orange crystals; yield: 0.46 g (15.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[I:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([I:10])=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc(Cl)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 5 ml of DMF. To this solution was added 0.76 g (7.32 mmol) of N-Iodosuccinimide. The solution was stirred 18 h at room temperature and then poured onto 100 ml of cool water. The formed precipitate was filtered, washed with water and dried to yield 1.2 g (76%) of a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:29]([O:38]C(OC(C)(C)C)=O)[C:28]([C:46]([F:49])([F:48])[F:47])=[CH:27][CH:26]=1>>[C:34]([O:33][C:31]([C:30]1[C:29]([OH:38])=[C:28]([C:46]([F:49])([F:47])[F:48])[CH:27]=[CH:26][C:25]=1[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:7]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(C(C)C)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)c1cc(C(C)C(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Yield: 45 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl 2-(4′-hydroxy-2-isopropyl-1,1′-biphenyl-4-yl)propanoate (290 mg, 0.97 mmol) obtained in Example (107-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (487 mg, 1.07 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (246 mg, three-step total yield: 45%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[S:24]([NH2:27])(=[O:26])=[O:25]>O1CCCC1>[NH2:27][S:24]([C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][Cl:8])(=[O:25])=[O:26]
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CCCCl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
144 mmol of triethylamine and then, dropwise, a solution containing 135 mmol of 4-chlorobutanoic acid chloride in 30 ml of tetrahydrofuran (THF), are added to a solution containing 96.4 mmol of 2-amino-5-methoxybenzenesulphonamide in 200 ml of THF. After stirring overnight at ambient temperature, the THF is evaporated off and the residue is taken up in water. Following extraction with ethyl acetate, the organic phase is washed and dried. After evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([O:29][C@@H:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)[CH:26]=[CH:25][N:24]=1.CC(O)=O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[CH:26]=[CH:25][N:24]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccnc(Cl)n2)C1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a stirred solution of the 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 165 mg, 0.55 mmol) and tert-butyl (3R)-3-[(2-chloropyrimidin-4-yl)oxy]pyrrolidine-1-carboxylate (164 mg, 0.55 mmol) in dioxane (2.7 ml) was added AcOH (66 μl, 1.15 mmol). The mixture was heated to 120° C. for 5 h, treated with additional portion of AcOH (66 μl, 1.15 mmol), and left to stir overnight. Additional AcOH (66 μl, 1.15 mmol) was then added and the resultant mixture was left to stir overnight. The mixture was then cooled to room temperature, diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash. (ethyl acetate/hexanes) to afford 80 mg (0.14 mmol, 26% yield) of tert-butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([OH:23])=O)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([N:37]([CH3:38])[CH3:36])=[O:23])[C:14]([F:17])([CH3:15])[CH3:16])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Product: CN(C)C(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
Prepared from 3-(1-{1-[(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoic acid and dimethylamine according to the procedure described in Preparation 22; Mass Spectrum: m/e=522 (M+1, 35Cl), 524 (M+1, 37Cl).