Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]1([CH:16]=[CH:17][C:18](Cl)=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([CH:17]=[CH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(Cl)C=CC1CCCCC1
Reactant: Nc1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc2[nH]c(C=CC3CCCCC3)nc2c1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a solution of 4-bromo-benzene-1,2-diamine (3.0 g, 16.1 mmol) in anhydrous toluene (50 ml) was added a solution of 3-cyclohexyl-acryloyl chloride (as prepared in STEP B above, 32.5 mmol) in toluene (5 ml). The resulting solution was stirred at 40° C. for 6 h. To the resulting solution was added p-toluenesulfonic acid (3.0 g, 16 mmol) and heated to reflux for 18 h. The resulting solution was concentrated. The residue obtained was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The layers were separated. The organic layer was washed successively with saturated sodium bicarbonate, water, brine, then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed using a silica gel to yield 5-bromo-2-(2-cyclohexyl-vinyl)-1H-benzoimidazole.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:20])=O.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:20][C:3]1[N:2]([CH3:1])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(=O)n(C)c(=O)[nH]c2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1ccc2c(=O)n(C)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
Into a round bottom flask was added methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.48 g, 2.1 mmol) dissolved in phosphoryl chloride (20.0 mL, 214 mmol). N,N-diethylaniline (0.99 mL, 6.2 mmol) was added followed by phosphorus pentachloride (0.22 g, 1.05 mmol). The reaction mixture was heated to 120° C. and stirred for 1 d. The mixture was then cooled to rt and concentrated. The residue was poured over ice and extracted with DCM (3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.12 g, 23%). LC-MS: (FA) ES+ 253; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=8.4 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.10 (dd, J=8.4, 1.5 Hz, 1H), 3.98 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:19]([NH2:20])=[CH:18][CH:17]=[N:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][N:15]1[C:19]([NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=[N:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1nccc1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Under cooling in an ice bath, 4-(trifluoromethyl)benzoyl chloride (8.26 g) was added dropwise to a chloroform (35 mL) solution that contained 1-methyl-1H-pyrazol-5-amine (3.50 g) and triethylamine (5.50 mL), and the obtained solution was then stirred for 2 hours. Thereafter, the reaction solution was diluted with chloroform, and was then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (6.75 g) in the form of a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[O:22]=[C:23]([CH3:33])[CH2:24][NH:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[O:22]=[C:23]([CH3:33])[CH2:24][N:25]([C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(O)Cc1ccsc1
Reactant: COC(=O)C(C)(C)NCC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)N(CC(C)=O)C(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
To a solution of thiophen-3-acetic acid (8.7 g) in dichloromethane (70 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.7 g), and the mixture was stirred for 10 minutes at room temperature. To the solution was added dropwise a solution of methyl 2-(2-oxopropylamino)isobutyrate (10.6 g) in dichloromethane (10 mL) at room temperature, and the mixture was then stirred for 24 hours at room temperature. After distilling off the solvent, water was added, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate. After distilling off ethyl acetate, 7.61 g of methyl 2-[N-(2-oxopropyl)thiophene-3-yl-acetylamino]isobutyrate was obtained.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C@H:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:14][C@H:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)SCC(CC(C)C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)C(CSC(C)=O)CC(C)C

Procedure:
2-Acetylthiomethyl-4-methylpentanoyl chloride and (L)-phenylalanine, ethyl ester are reacted in methylene chloride in the presence of diisopropylethylamine at a temperature below 0° according to the procedure of Example 26 to yield (±)-N-[2-(acetylthiomethyl)-4-methyl-1-oxopentyl]-L-phenylalanine, ethyl ester as an off-white foam.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][N:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[N:14]1[CH:18]=[N:17][N:16]=[CH:15]1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][N:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[N:14]1[CH:15]=[N:16][N:17]=[CH:18]1
Reactant: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2cccc(O)c2)n2cnnc2)cc1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a solution of 4-[(3-Benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (0.4 g, 1.05 mmol) in anhydrous THF/MeOH (20 mL) was added Pd—C (10% by wt., 0.04 g). The black suspension was then stirred under an atmosphere of hydrogen (balloon) for 16 h. The catalyst was removed by filteration through Celite® and exhaustively washed with THF. The filtrate was concentrated in vacuo to give a beige residue. Recrystallisation from EtOH gave STX333 as a colourless solid (0.27 g, 88%) after recrystallisation; δH (400 MHz, DMSO-d6) 4.97 (s, 2H), 6.68 (AA′BB′, 2H), 6.72-6.75 (m, 3H), 7.11 (m, 1H), 7.76 (AA′BB′, 2H), 8.77 (s, 2H), 9.49 (br s, 1H—exchanges with D2O); LRMS (FAB+) m/z (rel. intensity) 292 (100%, [M+H]), 223 (42, [M+H-triazole]); HPLC tR=2.22 min, (96%); HRMS (FAB+) Found 292.1198; C16H13N5O requires 292.1192;
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1cncnc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3cncnc3)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-[4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (example 45) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow oil. MS: 531.3 (MH+).
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][CH:24]=1
Reactant: Brc1ccc[se]1
Reactant: CCCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(-c3ccc[se]3)cc2)c(F)c1F

Procedure:
A mixture of 12.7 g (60.6 mmol) of 2-bromoselenophene, 17.7 g (60.6 mmol) of 2′,3′-difluoro-4′-propoxybiphenyl-4-ylboronic acid, 5.55 g (4.80 mmol) of tetrakis(triphenylphosphine)palladium(0) and 180 ml of 2 N sodium carbonate soln. in 600 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium chloride soln., and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). Further purification is carried out by recrystallisation from n-heptane:EtOH=3:1. 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)selenophene is obtained as a yellow solid.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH2:10].[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH:10][C:21]([C:11]12[CH2:20][CH:15]3[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]3)[CH2:18]1)[CH2:12]2)=[O:22]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1nc2c(s1)CCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2c(s1)CCC2)C12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine hydrochloride (400 mg, 2.27 mmol), 1-adamantanecarbonyl chloride (540 mg, 2.72 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol) and triethylamine (632 μL, 4.54 mmol) in 30 mL of THF was processed according to the method of Example 1A to afford the title compound: MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C@@H:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:5]#[N:6].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:1][C@H:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C@@H:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:5]#[N:6])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCCCCC[C@@H](O)C[C@H](C#N)c1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC[C@H](C[C@H](C#N)c1ccc(OC)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a solution of 559 mg (2.0 mmol) of (2S,4R)-4-hydroxy-2-(4-methoxyphenyl)decanenitrile in 5 ml of pyridine were added, with cooling with ice, a solution of 774 mg (4.1 mmol) of p-toluenesulfonyl chloride (TsCl) in 3 ml of pyridine and 24 mg (0.2 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP). This mixture was stirred at room temperature for 3 days. The pH of the reaction mixture was adjusted to 7 with diluted hydrochloric acid, and this reaction mixture was subjected to extraction with ether (150 ml). The resulting ether solution was washed with diluted hydrochloric acid and saturated sodium chloride aqueous solution, and then concentrated. The residue was separated and purified by column chromatography (Kieselgel 60, hexane/ethyl acetate=4/1), thereby obtaining 550 mg (yield 63%) of (2S,4R)-4-p-toluenesulfonyloxy-2-(4-methoxyphenyl)-decanenitrile.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:23][O:24][CH3:25])[CH2:4][O:5][C:6]1[C:10]2[CH:11]=[C:12]([O:15]CC3C=CC=CC=3)[CH:13]=[CH:14][C:9]=2[O:8][N:7]=1>CO.[C].[Pd]>[ClH:1].[NH2:2][CH:3]([CH2:23][O:24][CH3:25])[CH2:4][O:5][C:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[O:8][N:7]=1
Reactant: COCC(N)COc1noc2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COCC(N)COc1noc2ccc(O)cc12

Procedure:
To a suspension of 0.40 g of 3-(2-amino-3-methoxypropoxy)-5-benzyloxy-1,2-benzoisoxazole hydrochloride in 20 ml of methanol is added 0.1 g of 5% palladium carbon, and they are subjected to catalytic reduction at 20°-25° C. under atmospheric pressure. The 5% palladium carbon is removed from the reaction mixture by filtration, and the solvent is removed from the filtrate by distillation under reduced pressure. The residue obtained is crystallized from 2-propanol, and the crystals are collected by filtration, to obtain 0.16 g of colorless, crystalline 3-(2-amino-3-methoxypropoxy)-5-hydroxy-1,2-benzoisoxazole hydrochloride having a melting point of 187°-190° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[S:4][N:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)[CH3:16]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[CH:10]=1
Reactant: CC(Br)CCBr
Reactant: Cc1nsc2cc(O)ccc12
Product: Cc1nsc2cc(OCCCCBr)ccc12

Procedure:
In analogy to example 2.1, 3-Methyl-benzo[d]isothiazol-6-ol and 1,3-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-methyl-benzo[d]isothiazole as brown oil, MS: 300 (MH+, 1 Br).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH2:19][F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]CCCC
Reactant: N#CC(CCF)N=C(c1ccccc1)c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)(CCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
19.94 g (63.64 mmol, 85% purity) of rac-2-[(diphenylmethylene)amino]-4-fluorobutanonitrile from Example 66A were initially charged in 421 ml of abs. THF, and 25.71 ml (64.28 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 36.1 g (254.57 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 4.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 17.2 g of the target compound were obtained (78% of theory, 81% purity).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[F:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[F:21][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:22]=[C:23]([NH2:25])[S:24][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(F)c2)cc1
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(F)c2)cc1
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-1-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)ethanone (30-6, 0.60 g) and thiourea (0.160 mg, 2.05 mmol) in 95% EtOH (12.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure, and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)thiazol-2-ylamine (30-7, 0.450 g, 1.36 mmol) as yellow solids in 80% yield: 1H NMR (500 MHz, CDCl3) δ 6.98 (d, J=9.0 Hz, 2 H), 6.89 (d, J=9.0 Hz, 2 H), 6.60 (s, 1 H), 6.49 (d, J=10.9 Hz, 1 H), 6.41 (s, 0.1 H), 3.80 (d, J=3.4 Hz, 3 H), 2.26 (s, 3H). ESI-MS: m/z 331.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CCCc1nc(O)c2cc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(Cl)c2cc(Cl)ccc2n1
Yield: 58.1 %

Procedure:
Preparation D10, Step 3: 6-Chloro-2-propylquinazolin-4-ol (810 mg, 3.64 mmol, 1 eq), phosphorus oxychloride (3.30 mL, 35.1 mmol, 9.64 eq) and triethylamine (1.63 mL, 11.7 mmol, 3.21 eq) were mixed at room temperature then refluxed for 2.5 hours. The reaction was stripped 3 times from methylene chloride. The residue was dissolved in methylene chloride (25 mL) and rinsed 3 times with saturated sodium bicarbonate (25 mL), 1× with water (25 mL). The organic layer was dried (sodium sulfate) and stripped to an amber oil. Purified over silica gel in 9:1 hexanes/ethyl acetate to give 4,6-dichloro-2-propylquinazoline (510 mg) as a light-amber solid. Yield=58%. 1H NMR (400 MHz) (CD3OD) □ 7.98 (s, 1H); 7.98 (d, 1H, J=7 Hz); 7.93 (d, 1H, J=7 Hz); 3.00 (t, 2H, J=7 Hz); 1.90 (t of q, 2 H, J=7 Hz); 1.00 (t, 3H, J=7 Hz).
Reaction SMILES: C([Li])CCC.C[Si]([C:10]#[CH:11])(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].N>O1CCCC1.CCCCCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21]([C:10]#[CH:11])([OH:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: C#C[Si](C)(C)C
Agent: N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC1(O)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
In a dry ice-acetone bath, 40 ml of a 1.6 M hexane solution of n-butyllithium was added dropwise to a solution of 6.07 g of trimethylsilylacetylene in 100 ml of tetrahydrofuran. After the temperature was once elevated to 0° C., the mixture was cooled again in a dry ice-acetone bath and a solution of 5.97 g of 1-tert-butoxycarbonylpiperidin-3-one in 50 ml of tetrahydrofuran was added dropwise thereto. After 1 hour, aqueous ammonia chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 30% ethyl acetate/hexane. To the resulting compound were added 10 g of anhydrous potassium carbonate and 100 ml of methanol, followed by stirring for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated, to give 4.8 g of the title compound.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([OH:24])=[O:23])=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(=O)(=O)(O)O.[CH3:30]O>>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([O:24][CH3:30])=[O:23])=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CO
Reactant: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c([N+](=O)[O-])c21
Agent: O=S(=O)(O)O
Product: CCCCCCCCN1CCc2cc(C(=O)OC)c(C)c([N+](=O)[O-])c21

Procedure:
1-Octyl-5-carboxy-6-methyl-7-nitroindoline (1.4 g) was dissolved in methanol (30 ml), and conc. sulfuric acid (4.1 g) was added, which was followed by refluxing for 4 hr. Methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1/0-10/1) to give 750 mg of 1-octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline as crystals.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:4]1)=O.[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:35]=[CH:36][C:37]=1[F:38].Cl>>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]4[CH2:30][CH2:29][CH2:28]4)[C:14]([OH:16])=[O:15])[CH2:4]3)[CH2:44][CH2:43]2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1F
Agent: Cl
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)c(F)c3)CC2)[C@@H](c2ccsc2)C1
Yield: 65.1 %

Procedure:
The title compound was prepared from 21 mg (0.046 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-3-(cyclobutyl) propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 87, Step F) and 11.7 mg (0.046 mmol) of 4-(3-(3,4-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 119, Step C) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to provide 15.9 mg (77%) of the title compound: RF: 0.34 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 1.00-3.48 (m, 33H), 6.79-7.01 (m, 4H), 7.18 (m, 1H), 7.32 (m, 1H); ESI-MS 531 (M+H); HPLC A: 3.01 min.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N:13]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCc2cc(N3CCC3)ccc21
Temperature: 100 °C

Procedure:
5-fluoro-1-indanone (7.44 g, 49.5 mmol), Azetidine HCl (5.1 g, 54.4 mmol) and K2CO3 (13.6 g, 99 mmol) were taken up in 60 ml of DMSO. The reaction mixture was heated at 100° C. for 6 hours.