Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=C[C:9]=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([OH:49])=O)=[N:45][CH:46]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(NCC)C>CN(C)C=O>[CH2:10]([NH:6][C:47]([C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:46][N:45]=1)=[O:49])[CH3:9]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) was added to a solution of 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid (0.10 g) and diisopropylethylamine (50 μL) in dimethylformamide (1 mL) at room temperature. The resulting solution was stirred for 25 min, before diethylamine (70% in water, 50 μL) was added. The solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound as a foam-like solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][C:23]4[N:24]([C:30](=[O:32])[NH2:31])[CH2:25][CH2:26][CH2:27][C:28]=4[CH:29]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[N:16]1[CH:17]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23](=[N:22][CH:21]=2)[N:24]([C:30]([NH2:31])=[O:32])[CH2:25][CH2:26][CH2:27]3)[CH:19]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cncc(C4CCNCC4)c3)cnc21
Reaction time: 16 h
Yield: 122.3 %

Procedure:
To the 5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (19.3 mg, 0.04 mmol) in 1 mL of CH2Cl2 is added 1 mL of 4 M HCl in dioxane. The mixture is stirred for 16 h. The mixture is concentrated to give 16.5 mg of 6-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[CH:12]2[CH2:15][CH2:16][N:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C>[C:2]1([CH:1]([CH:8]2[C:13](=[O:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccccc2)N2CCC1CC2
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C1C2CCN(CC2)C1C(Cc1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-benzylidene-3-oxo-1-azabicyclo[2.2.2]octane (10 g) in diethyl ether (200 ml) at -10° C. under a nitrogen atmosphere was added a solution of 2M-benzylmagnesium chloride (30 ml, in tetrahydrofuran, 50 mmol) and diethyl ether (100 ml). The solution was stirred at -10° C. for 30 minutes and at ambient temperature for 16 h. A saturated solution of aqueous ammonium chloride (200 ml) was carefully added and the product extracted into ethyl acetate. The organic phase was dried (MgSO4) and evaporated to dryness. The residue was chromatographed on a column containing silica gel 60 (220-440 mesh ASTM) eluting with mixtures of 30%, 50% and 70% ethyl acetate in petroleum ether (bp 60°-80° C.). 2-(1,2-diphenylethyl)-3-oxo1- azabicyclo [2.2.2]octane was obtained as 1:1 mixture of stereoisomers by evaporating the appropriate fractions.
Reaction SMILES: [CH:1](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)=[CH:2]\[CH3:3].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:1](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]=[CH:12][C:11]([O:15][CH3:16])=[O:14])=[CH:2]\[CH3:3]
Reactant: C/C=C/c1ccccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C/C=C/c1ccccc1C=CC(=O)OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Under an argon atmosphere, 2-((E)-1-propenyl)bromobenzene (2.1 g, 11.0 mmol), methyl acrylate (4.5 mL, 50 mmol) and triethylamine (1 mL) were added to a solution (15 mL) of palladium (II) diacetate (11 mg, 0.05 mmol) and tris(2-methylphenyl)phosphine (60 mg, 0.2 mmol) in N,N-dimethylformamide, followed by stirring at 80° C. for 1 hour. Next, the reaction solution was filtered through Florisil, and the solvent contained in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/hexane=1/10) to give methyl 2-((E)-1-propenyl)cinnamate (740 mg, yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 20 g of 6-methoxy-1H-indole, 41.75 g of the hydrochloride of 4-piperidone monohydrate and 205 ml of methanolic 2 N potassium hydroxide was refluxed for 81/2 hours and was then stirred overnight at room temperature. The mixture was slowly diluted with water to a volume of 1.2 liters and crystallization was effected. The mixture was stirred for 30 minutes and was filtered and the recovered product was carefully rinsed with water and dried to obtain 23.05 g of 6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 193°-194° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[N:21]([CH2:33][CH3:34])[C:22]3[C:27]([C:28]=2[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:14][CH:13]=1.C(OC=O)(=O)C>C1COCC1>[C:29]([C:28]1[C:27]2[C:22](=[CH:23][C:24]([O:31][CH3:32])=[CH:25][CH:26]=2)[N:21]([CH2:33][CH3:34])[C:20]=1[C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:8]=[O:10])=[CH:13][CH:14]=1)#[N:30]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=CO
Agent: CC(=O)OC=O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCn1c(C#Cc2ccc(NC=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65° C. for 1 hour. This is cooled to 0° C. 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1H, is taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at 0° C. for 30 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The EtOAc layer is washed with saturated NaHCO3, followed by saturated brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (105 mg, 96%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=O)C.[OH-].[Na+].[C:9](Cl)(=[O:23])[CH2:10]CCCCCCCCCCCC.[C:25]([NH:40][C@H:41]([C:43]([OH:45])=[O:44])[CH3:42])(=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].S(=O)(=O)(O)O>O.C(O)(C)(C)C>[N:1]([CH2:2][CH2:4][OH:6])([CH2:10][CH2:9][OH:23])[CH2:26][CH2:25][OH:39].[C:25]([NH:40][C@H:41]([C:43]([OH:45])=[O:44])[CH3:42])(=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: OCCN(CCO)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35.6 g of L-alanine was dissolved in 187.7 g of water, 42.3 g of tert-butanol (content of organic solvent: 18.4 wt %) and 6.8 g of sodium hydroxide to prepare an aqueous solution at pH 10. Then, this aqueous solution was added with 98.7 g of myristoyl chloride over about 1 hour, while a pH was adjusted to 10 by using 27% NaOH. During this operation, the reaction temperature was maintained at 25° C. After the addition of the acid chloride, the reaction mixture was stirred at the same temperature for about 1 hour. About 26% of N-myristoyl-L-alanine was contained in 461 g of the reaction mixture obtained, and the acylation purity was 97.6%. Further, the resulting reaction mixture was adjusted to pH 1.7 with addition of 29.4 g of 75% sulfuric acid and heated to 60° C. After stirring for 15 minutes, the reaction mixture was left standing, and the reaction mixture separated into an organic layer (176 g) and an aqueous layer (313 g) within several minutes. The resulting organic layer was further added with 250 g of 10 wt % aqueous tert-butanol, stirred and left standing for separation in the same manner. The resulting organic layer was neutralized to pH 7.0 with 90% aqueous triethanolamine to obtain an about 30% solution of N-myristoyl-L-alanine triethanolamine salt (containing tert-butanol), and then the tert-butanol was evaporated by vacuum concentration in the same manner as in Example 1 (400 g of water was added). The concentration of the salt was adjusted to 30% to obtain 585 g of N-myristoyl-L-alanine triethanolamine salt solution. This aqueous solution had a Cl content of less than 0.05%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: OCC(O)CO
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OC1COC(c2cccc(Cl)c2)OC1
Yield: 42.2 %

Procedure:
A mixture of 3-chlorobenzaldehyde (28.1 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and p-toluenesulfonic acid (0.1 g) in 150 ml of benzene was heated at reflux under a Dean-Stark apparatus until water was no longer collecting (3.6 ml). The solution was cooled, washed with 2% sodium bicarbonate solution (2 × 100 ml) and with water (2 × 100 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The oil remaining was distilled to give 18.1 g of colorless liquid which distilled at a pot temperature of 124°-128° C under 1 × 10-4 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([OH:17])=[O:16]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(COc2cncc(Cl)c2)cc1
Yield: 53.6 %

Procedure:
To a suspension of 5-chloro-3-hydroxypyridine (0.6 g, 4.6 mmol) and potassium carbonate (1.27 g, 9.2 mmol) in acetone (10 mL) was added 4-carboxybenzylbromide (1.0 g, 4.6 mmol). The reaction was heated at reflux for 18 hours. After cooling, the reaction mixture was partitioned between EtOAc (80 mL) and saturated aqueous ammonium chloride solution (140 mL). The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford the title compound (0.65 g, 53%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH2:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:54][CH:47]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCCCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC2CCCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with cycloheptylamine (Aldrich) to give the title product. LC-MS (ES+) 760 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]#[C:13][CH2:14][CH2:15][C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cccc(CCC#Cc2nc(-c3ccccc3)cs2)c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cccc(CCCCc2nc(-c3ccccc3)cs2)c1
Yield: 75.6 %

Procedure:
10% Palladium on charcoal (215 mg) was added to a solution of 3-(4-(4-phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile (430 mg, 1.37 mmol) in ethanol (15 mL), the reaction mixture was put under ˜2 kg H2-pressure for 48 h. The reaction mixture was filtered through a celite bed and washed thoroughly with EtOAc. The solvent was concentrated under reduced pressure to obtain 3-(4-(4-phenylthiazol-2-yl)butyl)benzonitrile (330 mg, 76%) as colorless viscous liquid. 1H NMR (300 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.50-7.33 (m, 8H), 3.13-3.08 (t, J=7.5 Hz, 2H), 2.75-2.70 (t, J=7.5 Hz, 2H), 1.93-1.85 (m, 2H), 1.83-1.75 (m, 2H). MS (ESI) m/z: Calculated for C20H18N2S: 318.12. found: 319.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:13])([CH3:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[OH-].[Na+]>[NH2:11][CH2:10][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([OH:13])[CH3:12]
Reactant: CC(O)(CC#N)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(CCN)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 135 %

Procedure:
A solution of 3-(3-chlorophenyl)-3-hydroxybutanenitrile (400 mg, 2.04 mmol) in dry THF (10 mL) was cooled to 0° C. LiAlH4 powder (155 mg, 2 equiv.) was added. After 5 min, the mixture was warmed to rt and stirred for 4 h. The mixture was then heated to reflux for 6 h. The mixture was diluted with 1 M aq NaOH (30 mL) and extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 extracts were washed with brine, dried over Na2SO4 and concentrated to afford crude 4-amino-2-(3-chlorophenyl)butan-2-ol (550 mg, quant) which was used without purification. LC-MS Method 1, tR=0.88 min, m/z=200, 202.
Reaction SMILES: [NH2:1][C:2]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1.[CH2:21]([O:28][C:29]([N:31]([CH2:33][C:34](O)=[O:35])[CH3:32])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([N:31]([CH2:33][C:34]([NH:1][C:2]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1)=[O:35])[CH3:32])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(N)CCc2cc(OC)c(OC)cc2C1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NC(=O)CN(C)C(=O)OCc2ccccc2)CCc2cc(OC)c(OC)cc2C1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a solution of ethyl 2-amino-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate (430 mg, 1.5 mmol), N-benzyloxycarbonylsarcosine (357 mg, 1.6 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride in dichloromethane (5 ml) was added triethylamine (160 mg, 1.6 mmol) under stirring at 0° C. After stirring for 2 hr, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 1N hydrochloric acid, sat. sodium bicarbonate, sat. sodium chloride, dried, and evaporated. The residue was purified with silica gel column chromatography [eluent; hexane-ethyl acetate (1:1 to 1:2)] to give the titled compound (550 mg, 74%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].I[C:43]1[N:44]([CH3:52])[N:45]=[C:46]2[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]2>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH3:1][C:2]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:19][C:18]([C:43]4[N:44]([CH3:52])[N:45]=[C:46]5[C:51]=4[CH:50]=[CH:49][CH:48]=[CH:47]5)=[N:17][C:16]=3[CH:15]=2)[CH2:11][CH2:12]1)([CH3:6])[C:3]([NH2:5])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Cn1nc2ccccc2c1I
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1nc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Yield: 22.4 %

Procedure:
To a degassed mixture of 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide (270 mg, 0.389 mmol), 3-iodo-2-methyl-2H-indazole (95 mg, 0.368 mmol), copper(I) thiophene-2-carboxylate (70 mg, 0.368 mmol) in dioxane (2.3 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol). The reaction mixture was reacted in the CEM microwave at 140° C. for 30 min. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH and the desired product was then eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 176 (44 mg, 29%). LCMS: M+H+=535.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, 1H), 7.67 (d, 1H), 7.47 (s, 1H), 7.31 (t, 1H), 7.19 (t, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 4.60 (s, 3H), 4.06 (m, 4H), 3.88 (s, 2H), 3.84 (m, 4H), 2.49-2.62 (m, 8H), 1.08 (s, 6H)
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:8]=2[CH:26]=1)[CH3:3].[ClH:27]>CO.C(O)C>[ClH:27].[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:8]=2[CH:26]=1)[CH3:1]
Reactant: CC(C)c1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)c1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl 4-[6-(1-methylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinecarboxylate D34 (0.71 g) in methanol (30 mL) was treated with a saturated solution of hydrogen chloride in ethanol (10 mL). The mixture was stirred for 1 hour when the solvent was removed to give the title compound as a white solid (0.59 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)C.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=C1CCC(=O)O1
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
35.2 g of 4-phenyl 2-amino thiazole are dissolved in 350 ml of boiling 1-2 dichloroethane. To this solution add 20 g of succinic anhydride. The amide formed crystallizes; keep under reflux for five hours and filter. By recrystallization from alcohol there are recovered 39 g (70%) of the product of the formula ##STR12##
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(Oc2ccc(N)cc2)c1
Yield: 25.8 %

Procedure:
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAcn70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([CH3:26])[N:20]=1>>[Cl:25][C:24]1[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[N:20][C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: Cc1ncc(Cl)c(N)n1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1ncc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-5-chloro-2-methylpyrimidine (42 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.58 (d, J=1.5 Hz, 1H), 8.72-8.65 (m, 2H), 7.42 (dd, J=6, 5.1 Hz, 1H), 6.70 (s, 1H), 5.32 (s, 2H), 1.70 (s, 3H).