Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1([CH2:24][OH:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1([CH:24]=[O:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(C=O)CCOCC1
Temperature: -65 °C
Reaction time: 0.05 h
Yield: 92.6 %

Procedure:
Anhydrous dimethyl sulfoxide (3.0 mL, 42.2 mmol) was added to a −65° C. solution of oxalyl chloride (2.0 mL, 22.9 mmol) in anhydrous dichloromethane (100 mL) and allowed to stir at −65° C. under N2 blanket for 3 minutes, after which time a solution of (4-hydroxymethyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (4.89 g, 21.1 mmol) in anhydrous dichloromethane (25 mL) was added. When 25 minutes had elapsed, triethylamine (14.7 mL, 105.5 mmol) was added and the reaction solution allowed to stir for a further 20 minutes at −65° C.; then the cold bath was removed and the reaction warmed to ambient temperature, washed with saturated aqueous sodium chloride (500 mL), dried (MgSO4), and evaporated to afford 4.48 g of clear yellow viscous liquid which was used without further purification. LRMS (ESI) m/z 230.2 [(M+H)+, calcd for C11H20NO4230.3].
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[CH:6]([S:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](C)(C)[O:15][SiH2]C(C)(C)C)=[CH:10][CH:9]=1.B(F)(F)F.CCOCC.Cl>C(#N)C.O>[Cl:34][C:2]([Cl:1])([Cl:35])[CH2:3][O:4][C:5](=[O:33])[CH:6]([S:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: Cl
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid 2,2,2-trichloro-ethyl ester (5.47 g, 9.43 mmol) in anhydrous acetonitrile (200 mL) was dropwise added BF3×Et2O (1.10 mL, 9.43 mmol) at 0° C. The mixture was stirred for 30 min. 2N aq. HCl (50 mL) and H2O (100 mL) were added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4) and evaporated to give the crude product which was purified by flash chromatography using DCM/MeOH 95:5 as the eluent. The product was obtained as an (3.62 g, 82.5%). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, 2H), 7.10 (d, 2H), 7.01 (m, 2H), 6.87 (t, 2H), 4.65 (d, 1H), 4.56 (m, 3H), 3.48 (dd, 1H), 3.12 (dd, 1H), 2.73-2.91 (m, 5H). Mass Spectrum: M−H+ 464.90.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[O:8]1[CH2:12][CH2:11][CH:10]([CH:13]=O)[CH2:9]1.CN(C=[O:19])C>O>[O:6]1[CH2:7][CH2:3][CH:4](/[CH:13]=[CH:10]/[C:9]([O:8][CH2:12][CH3:11])=[O:19])[CH2:5]1
Reactant: O=CC1CCOC1
Reactant: CN(C)C=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)/C=C/C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a 0° C. mixture of sodium hydride (60% in mineral oil) (382 mg, 9.40 mmol) in DMF (15.0 mL) (THF may also be used) was added triethyl phosphonoacetate (1.72 mL, 8.68 mmol) dropwise. The resulting mixture was warmed to room temperature and stirred for 30 minutes, then was re-cooled to 0° C., at which time a solution of tetrahydrofuran-3-carbaldehyde (724 mg, 7.23 mmol) in DMF (4.0 mL) was added dropwise. The resulting mixture was stirred at this temperature for 1.5 hours, at which time the mixture was diluted with water and the product was extracted with ether. The combined extracts were washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-40% ethyl acetate in hexanes) afforded the product (640 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28]>>[O:12]=[C:7]1[C:6]2[NH:13][CH:14]=[CH:15][C:5]=2[C:4]2[CH:3]=[C:2]([NH:1][S:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)(=[O:29])=[O:28])[CH:11]=[CH:10][C:9]=2[NH:8]1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCC(=O)O
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3cccs3)cc2c2cc[nH]c12
Yield: 20.3 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 39 mg (0.21 mmol) of thiophene-2-sulfonyl chloride. After recrystallization from methanol, 17 mg (21%) of 4-oxo-8-(thiophene-2-sulfonylamino)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: COC1[CH:24]=[CH:23][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20]C=CC=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=CC=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[C:31](#N)[CH3:32]>CCCCCC>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[C:6]([C:32]3[CH:31]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[C:23]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:20]=[CH:21][CH:16]=2)=[CH:13][CH:12]=1
Reactant: C1CCNCC1
Reactant: CC#N
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCCCCC
Product: COc1ccc(-c2cccc(CN3CCCCC3)c2-c2ccc(OC)cc2)cc1
Yield: 85 %

Procedure:
4,4′-dimethoxytrityl chloride (0.83 g, 2.45 mmol) (Tokyo Chemical Industry Co., Ltd.) was dissolved in acetonitrile (15 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (1.24 g, 14.6 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 1 hour, and the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.)→chloroform (Wako Pure Chemical Industries, Ltd.):n-hexane (Wako Pure Chemical Industries, Ltd.)=1:4 as an eluent), to thereby obtain the title compound (0.81 g, 85% yield).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:31]1([NH:36][C:37]([NH2:39])=[NH:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(C)([O-])C.[K+].CCOCC>O1CCCC1.O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:39]=[C:37]([NH:36][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:38]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.5 g, 8.9 mmol) in tetrahydrofuran (36 mL, 0.25 M) was added N-cyclopentylguanidine hydrochloride (1.89 g, 11.6 mmol), followed by solid potassium tert-butoxide (2.6 g, 23.2 mmol) in two portions. The resultant solution was heated to reflux for 23 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (3.7 g, 91%) as an off white solid. 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.68 (d, 1H), 7.59 (dd, 2H), 7.27 (t, 1H), 7.10 (t, 2H), 6.24 (d, 1H), 5.99 (d, 1H), 5.96 (d, 1H), 5.01 (d, 1H), 4.28 (m, 1H), 3.97 (m, 1H), 2.12–1.99 (m, 4H), 1.79–1.44 (m, 12H); 13C NMR (CDCl3) δ 163.12 (d, JCF=246.6 Hz), 162.09, 161.53, 156.67, 152.15, 142.66, 141.09, 131.46 (d, JCF=8.0 Hz), 129.92 (d, JCF=3.1 Hz), 128.39, 115.45(d, JCF=21.3 Hz), 108.68, 107.13, 105.15, 90.13, 53.84, 52.87, 33.50, 33.30, 24.05, 23.70; 19F NMR (CDCl3) δ −113.49; MS m/z 457 (M+1); Anal. Calcd for C27H29FN6: C, 71.03; H, 6.40; N, 18.41. Found: C, 71.20; H, 6.37; N, 18.52.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:50]3[O:49][C:48]([NH:51][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=4)=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccc(C)nc3)nc12

Procedure:
From 6-methyl-nicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 378 (M+H+, 100).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)#N.[OH-:15].[K+].S(OC)([O:20][CH3:21])(=O)=O>CN(C=O)C.C(O)C.O>[CH3:13][C:10]1([CH3:14])[O:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]([O:20][CH3:21])=[O:15])[CH2:8][O:9]1
Reactant: [OH-]
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)OCC(CCCCC#N)CO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COC(=O)CCCCC1COC(C)(C)OC1
Yield: 52 %

Procedure:
The crude nitrile 23 obtained above (79 g, 0.401 mol) is heated under reflux for 24 h with potassium hydroxide (31 g, 0.47 mol), 250 mL ethanol and 100 mL water. 300 mL water is added and most of the ethanol is distilled off. 200 mL n-propanol is added and the mixture is heated under reflux for 2 d. After cooling, 300 mL water is added and the mixture is extracted with 2×250 mL toluene. The toluene layers are washed with 250 mL water. The aqueous layers are evaporated, the last traces of water are removed at 100° C. (0.2 mmHg). The solid residue is stirred for 24 h with 300 mL DMF and 62 mL dimethyl sulfate (0.66 mol). The mixture is evaporated and to the residue there is added 500 mL toluene and 300 mL water. The layers are separated and the toluene layer is washed with 300 mL water. The aqueous layers are extracted with 250 mL toluene. The combined organic layers are dried and evaporated end the residue is purified by bulb-to-bulb distillation to give ester 24 (47.7 g, 0.207 mol, 52%) with bp 120° C. (0.2 mmHg). 1H-NMR (CCl4): δ 1.0-1.9 (m), 1.25 (s) and 1.30 (s) (13H), 2.2 (bt, 2H), 3.2-3.9 (m) and 3.6 (s) (7H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([F:34])[CH:28]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[C:35]#[N:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>C(#N)C>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:45]([NH:44][C:41]4[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=4)=[O:46])=[C:29]([F:34])[CH:28]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[C:35]#[N:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCc1ccccc1

Procedure:
After adding 210 mg of toluene and 20 ml of acetonitrile to 6.95 g of the 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained in Production Example 8, the mixture was heated to reflux. Next, 2.67 ml of 4-fluorophenyl isocyanate was added and the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and dried under reduced pressure to obtain 7.45 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[O:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 64 %

Procedure:
A mixture of crude ethyl di-(4-chlorophenyl)methyloxyacetate (9 g.), sodium hydroxide (5 g.), ethanol (150 ml.) and water (5 ml.) was heated under reflux for 16 hours. The mixture was evaporated and the residue was diluted with water (100 ml.) and ether (30 ml.). The ether extracts were discarded and the aqueous phase was acidified to pH 2-3 with 20% v/v hydrochloric acid. The mixture was extracted with ether and the extracts were dried (MgSO4) and evaporated. The residual solid obtained was crystallised from a mixture of ethyl acetate and petrol to give di-(4-chlorophenyl)methyloxyacetic acid, m.p. 108°-110°, in 64% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][C:33](=[O:34])[C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:37][CH:36]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)Sc2cccn3c(=O)c(C(=O)OCC)cnc23)cc1
Yield: 51.3 %

Procedure:
To a mixture of 0.8 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1, 0.5 g of powdery potassium carbonate and 25 ml of acetone is added 0.7 g of 4-n-butoxybenzoyl chloride with stirring, and the resultant mixture is stirred at room temperature for 2 hours. The resultant precipitate is filtered and distributed in water-chloroform. The chloroform layer is washed with saturated brine, dried over sodium sulfate and concentrated. The residue (1.1 g) is chromatographed on a column of silica gel, eluting with ethyl acetate. Concentration of the eluate affords 0.7 g of the titled compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[C:11](#[N:13])[CH3:12].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[N:22]=[C:23]=[S:24].CN1[CH:33]=[CH:32][C:30](=[O:31])N(C)C1=O>C1COCC1.CCO>[C:11]([C:12]1[CH:33]=[CH:32][C:30](=[O:31])[N:22]([C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[C:23]=1[S-:24])#[N:13].[Na+:10]
Reactant: Fc1cccc(F)c1N=C=S
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(=O)n(-c2c(F)cccc2F)c1[S-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (351 ml of a 1M solution in THF, 351 mmol) in THF (150 ml) was cooled to −78° C. and acetonitrile (30 ml) was added. After 20 min, 2,6-difluorophenyl isothiocyanate (30.0 g, 175.5 mmol) was added slowly over 5 min. The reaction mixture was allowed to warm slowly to r.t. over 2 h. EtOH (100 ml) was added followed by 1,3-dimethyluracil (27.0 g, 193.5 mmol) and the mixture heated to reflux for 18 h. After cooling, the mixture was concentrated in vacuo to a volume of approx. 150 ml and EtOH (75 ml) was added. This mixture was cooled and Et2O (approx. 750 ml) was added slowly to give a pale yellow precipitate. The solid was filtered off, washed with Et2O (2×100 ml) then dried to give the title compound as a yellow/pale brown solid (49.0 g, 86%). δH (DMSO-d6) 7.43-7.33 (1H, m), 7.23 (1H, d, J 9.2 Hz), 7.13-7.06 (2H, m), 5.64 (1H, d, J 9.2 Hz). LCMS (ES+) RT 7.0 minutes, 265 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[CH:27][N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[N:26]=[CH:27][N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (85.0 mg, 0.247 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (68.3 mg, 0.247 mmol) and HATU (94 mg, 0.247 mmol) in DMF (5 ml) was added diisopropylethyl amine (0.086 ml, 0.493 mmol) and the reaction mixture was stirred for 30 minutes at rt. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (97 mg, 0.161 mmol, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.43-7.53 (m, 1H), 7.39 (t, 1H), 5.47 (s, 2H), 4.46 (d, 2H), 3.35 (t, 2H), 0.59-0.81 (m, 2H), −0.12 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:4][CH2:5][O:6][CH3:7].[C:18](Cl)(Cl)=[O:19].[CH3:22][O:23][C:24](=[O:34])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:26]>>[CH3:22][O:23][C:24]([C@@H:25]([NH:26][C:18](=[O:19])[NH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:4][CH2:5][O:6][CH3:7])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34]
Reactant: COCOc1c(N)cc(OC)cc1C(C)(C)C
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: COCOc1c(NC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)cc(OC)cc1C(C)(C)C

Procedure:
(2-Amino-4-methoxy-6-tert-butylphenoxy)methoxymethane, phosgene and L-phenylalanine methyl ester were treated in the same manner as described in Example 16 (1) to give {2-[3-((1S)-1-methoxycarbonyl-2-phenylethyl)ureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.[C:23](Cl)(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[C:23]([O:15][CH2:14][C:3]1[CH:4]=[C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[O:6][C:2]=1[CH3:1])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1cc([Si](CC)(CC)CC)oc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyl-2-triethylsilyl-4-furylmethanol (208 mg. 0.92 mmol) and triethylamine (121 mg, 1.20 mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon was added lauroyl chloride 302 mg, 1.38 mmol). This solution was allowed to warm gradually to room temperature and quenched with a 10% aqueous HCl solution. The organics were extracted into hexanes and the combined fractions were washed with a saturated aqueous solution of sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: C(O[BH-](O[C:11](=O)[CH3:12])OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].[CH3:24][C:25]([CH3:27])=O.[OH-].[Na+]>C1COCC1.O.C(O)(=O)C>[CH:25]([N:19]([C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[O:16][CH3:15])[C:12]1[CH:11]=[CH:20][CH:18]=[CH:17][CH:23]=1)([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N(c1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 119.1 %

Procedure:
Sodium triacetoxyborohydride (27.9 g, 134 mmol) is added portionwise over 45 minutes to a 0° C. solution of 2-methoxyaniline (12.5 g, 101 mmol) in THF (100 mL), acetone (7.82 mL, 106 mmol) and acetic acid (5.9 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is cooled to 0° C. and then water (50 mL) is added slowly followed by 50% aqueous sodium hydroxide solution (20 mL) and the resultant mixture stirred for 1.5 h. The organics were removed and the residual aqueous phase diluted with water (30 mL) and extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to afford N-Isopropyl-N-(2-methoxy-phenyl) aniline (14.51 g) as an amber oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ6.91 (t, 1H, J=7.6), 7.01 (d, 1H, J=7.6), 6.68 (t, 2H, J=7.9), 3.88 (s, 3H), 3.66 (m, 1H, J=6.8), 1.28 (d, 6H, J=6.8).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[S:22][CH:21]=[C:20]([CH3:23])[C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[S:22][CH:21]=[C:20]([CH3:23])[C:18]=2[N:19]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3c(C)csc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred suspension of NaH (16 mg, 0.4 mmol) in dry THF (2 mL) was added 2,4,6-trimethyl phenol and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (87 mg, 0.4 mmol) in dry THF (2 mL) at 0° C. and slowly warmed up to room temperature. After stirring the reaction for 2 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1) to give the product as a white solid (136 mg, 90%):