Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([O:14][C:15]([NH:17][C:18](=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>N1CCCCC1.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][CH:18]([CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: COC(=O)C(=Cc1cccc(OC)c1)NC(=O)OC(C)(C)C
Reactant: COc1cccc(S)c1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)C(NC(=O)OC(C)(C)C)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Temperature: 60 °C

Procedure:
A solution of 0.091 g (0.65 mmol) of 3-methoxy-benzenethiol in 4 drops of piperidine is stirred at room temperature for 5 minutes. A quantity of 0.200 g (0.65 mmol) of 2-tert-butoxycarbonylamino-3-(3-methoxyphenyl)acrylic acid, methyl ester of Example 30 is added and the solution is heated at 60° C. for 24 hours. Ethyl acetate (120 mL) is added and the solution is washed with 3×80 mL of 1N sodium hydroxide and brine (80 mL). After drying (magnesium sulfate), the solution is evaporated and the residue is purified by silica gel chromatography, eluting with 20% ethyl acetate-hexane to give the product as an inseparable mixture of diastereomers; wt 0.26 g (89%);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C@H:15]2[CH2:19][CH2:18][C@@:17]3([CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[NH:16]2)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:61][CH2:62][CH2:63]O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:63][CH2:62][F:61])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]2[CH2:19][CH2:18][C:17]3([CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[NH:16]2)[CH:10]=1
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc(O)ccc4F)ccn3)N2)C1=O
Reactant: OCCF
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCC2(CCC(c3cc(-c4cc(OCCF)ccc4F)ccn3)N2)C1=O
Temperature: 120 °C

Procedure:
To a Smith microwave vial was added (2R,5S)-2-[4-(2-fluoro-5-hydroxy-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 134) (66.5 mg, 0.1900 mmol), triphenyl phosphine (102.19 mg, 0.3900 mmol), Di-tert-butyl azodicarboxylate ((89.71 mg, 0.3900 mmol) and 2-fluoroethanol (0.02 mL, 0.2900 mmol) in THF (0.5000 mL). Toluene (1 mL) was added. The reaction mixture was heated by microwave at 120° C. for 45 min. The reaction mixture was eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave colourless oil. The crude residue was purified by silica gel chromatography (KPNH silica 11 g) eluting with ethyl acetate in iso-hexane (10-100%) followed by methanol in ethyl acetate (0-18%). Evaporation of desired fractions gave colourless oil. It was further purified by a ChiralPak IA column eluting with ethanol/n-heptane (20%:80%) to give 2R,5S)-2-[4-[2-fluoro-5-(2-fluoroethoxyl)phenyl]-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one;
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C@H:7]([C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)[N:6]1[C:27](=[O:30])[CH2:28]Cl)=O.[CH3:31][NH2:32]>CO>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C@@H:7]3[C:8]4[NH:9][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=5[C:16]=4[CH2:17][C@@H:5]4[C:3](=[O:2])[N:32]([CH3:31])[CH2:28][C:27](=[O:30])[N:6]34)=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1C(=O)CCl
Reactant: CN
Solvent: CO
Product: CN1CC(=O)N2[C@H](c3ccc4c(c3)OCO4)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Temperature: 52.5 °C
Reaction time: 5 h

Procedure:
Cis-1 -benzo [1,3 ]dioxol-5 -yl-2-(2-chloro-acetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (30 g) was taken in methanol (450 ml). The resultant mixture was heated to 35-40° C. and aqueous methyl amine (27 ml; 40%) was added. The reaction mixture was stirred at 50-55° C. for 5 hours and then cooled to 10-15° C. with continuous stirring for 0.5 hours. The solid so obtained was filtered and dried to afford (6R,12aR) 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino [1′,2′:1,6] pyrido[3,4-b]indole-1,4-dione.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[C:5](=[O:23])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]CC2C=CC=CC=2)[O:10]1)[CH2:2][CH3:3]>C(O)(=O)C.[Pd].C(O)C>[CH2:24]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:23])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[O:10]1)[CH2:25][CH3:26]
Reactant: CCCN(CCC)C(=O)COCC1CCC(COCc2ccccc2)O1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN(CCC)C(=O)COCC1CCC(CO)O1
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 10.9 g of N,N-dipropyl-2-[[tetrahydro-5-[(phenylmethoxy)methyl]-2-furanyl]methoxy]acetamide (0.03 mole) in 125 ml of glacial acetic acid is added 2.5 g of 10% palladium on carbon. The mixture is hydrogenated at 55 psi over a period of 18 hours (debenzylation reaction taking up 98% of the calculated theory). The mixture is removed and the Pd/C filtered through a pad of "celite" filter aid. The acetic acid is then removed in vacuo yielding a pale yellow oil. The resulting oil is dissolved in 100 ml of ethanol and evaporated. The oil is then redissolved in ethanol and again evaporated in vacuo. The oil is then taken up in 200 ml of chloroform and washed with 100 ml of saturated NaHCO3 solution, 150 ml of water and finally with 200 ml of saturated NaCl solution. The CHCl3 layer is separated, dried over anhydrous Na2SO4 and then the CHCl3 is removed in vacuo yielding 7.6 g of crude product whih is vacuum distilled and the fraction distilling at 180°-183° @ 0.4 mm is collected yielding 7.1 g (87%) of the above compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[O:39][C:40]([CH3:43])=[N:41][N:42]=3)=[CH:34][CH:33]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:58][O:59][CH2:60][C@H:61](O)[CH3:62]>C1(C)C=CC=CC=1>[CH3:58][O:59][CH2:60][C@@H:61]([O:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[O:39][C:40]([CH3:43])=[N:41][N:42]=3)=[CH:36][CH:37]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:62]
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 237.6 %

Procedure:
Triphenyl phosphine (21 g, 80 mmol, 2.8 equiv.) was added to a stirring solution of Methyl 3-hydroxy-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoate (Intermediate 7) (9.3 g, 28.52 mmol, 1 equiv.) in toluene (100 mL) under nitrogen atmosphere at room temperature. The mixture was heated to 90° C. for 30 min. A mixture of Diisopropylazadicarboxylate (DIAD) (11.52 g, 57 mmol, 2 equiv.) and (R)-(−)-1-Methoxy-propan-2-ol (3.8 g, 42.8 mmol, 1.5 equiv.) in toluenene (50 mL) was added to the above reaction mixture at 90° C. and the reaction mixture was stirred for 3 h at 100° C. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum and purified by column chromatography to get (5)-Methyl 3-[(1-methoxypropan-2-yl)oxy]-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (Intermediate 8) as thick liquid (27 g). Sodium hydroxide (3.43 g, 85.92 mmol, 3 equiv.) in water (55 mL) was added to a stirring solution of (9-Methyl 3-[(1-methoxypropan-2-yl)oxy]-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (crude) (Intermediate 8) in methanol (110 mL) in round bottomed flask. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion, methanol was removed under vacuum and water was added. The reaction mixture was filtered. Filtrate was washed with ethyl acetate. The aqueous layer was acidified and extracted with DCM twice. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate, filtered and concentrated in vacuum to furnish title acid as thick liquid (9.5 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[N:14]1([C:2]2[N:11]=[C:10]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Clc1ccc2nc(N3CCCCC3)nc(N3CCCCC3)c2c1

Procedure:
Four grams of 2,4,6-trichloroquinazoline was dissolved in 50 ml of tetrahydrofuran. The solution was cooled in an ice bath and 20 ml of piperidine was added with constant stirring. The reaction mixture was heated at reflux overnight and the solid which had precipitated was removed by filtration. The filtrate was evaporated to dryness and diluted with water. The oil which separated crystallized upon scratching. The solid was collected by filtration and recrystallized from ethanol to give 4.2 g of 2,4-bispiperidino-6-chloroquinazoline; m.p. 115°-118°. The following analytical data were obtained:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11](Cl)=[C:12]3[C:13](=[O:36])[C:14]4[C:19]([C:6]([C:7]=23)=[N:5]1)=[C:18]([O:20]CC1C=CC=CC=1)[CH:17]=[CH:16][C:15]=4[O:28]CC1C=CC=CC=1.[CH3:38][N:39](CC1C=CC=CC=1)[CH2:40][CH2:41][NH2:42]>>[NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH:42][CH2:41][CH2:40][NH:39][CH3:38])=[C:12]3[C:13](=[O:36])[C:14]4[C:19]([C:6]([C:7]=23)=[N:5]1)=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=4[OH:28]
Reactant: NCCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(OCc3ccccc3)ccc(OCc3ccccc3)c1-2
Reactant: CN(CCN)Cc1ccccc1
Product: CNCCNc1ccc2c3c(nn2CCN)-c2c(O)ccc(O)c2C(=O)c13

Procedure:
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-bis-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one with N-methyl-N-(phenylmethyl)-1,2-ethanediamine as described in Example 78 gives the product; mp 169°-172° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[CH3:15][N:16]([CH2:17][CH2:18][OH:19])[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CNCCO
Product: Cc1oc(-c2ccccc2)nc1CN(C)CCO

Procedure:
The title compound was prepared from 4-chloromethyl-5-methyl-2-phenyloxazole (10 g) and 2-(methylamino)ethanol (36 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:31][C:32]([NH2:34])=[O:33]>CN(C)C=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:31][C:32]([NH2:34])=[O:33])[C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NC(=O)CCl
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(cn1CC(N)=O)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo-[3,4-d][2]benzazepine were added to an ice-cooled solution of 1.6 g (14.2 mmol) of potassium t-butoxide in 60 ml of dry dimethylformamide. After stirring at 0° C. for 15 minutes, 1.4 g (15.0 mmol) of 2-chloroacetamide were added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a red residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 50% ether in tetrahydrofuran) gave 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as a yellow solid. Recrystallization from ethyl acetate gave colorless needles, mp 142°-145° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.Cl.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[C:19]([CH:22]=1)[C:20]#[N:21]>C(N(CC)CC)C>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:6]([C:4]2[C:3]3[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=3[S:1][CH:5]=2)=[O:8])[CH:16]=[CH:17][C:18]=1[O:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][OH:27])#[N:21]
Reactant: CC(C)(CO)COc1ccc(N)cc1C#N
Reactant: O=C(O)c1csc2c1CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(CO)COc1ccc(NC(=O)c2csc3c2CCCC3)cc1C#N
Yield: 58.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.78 g) and 5-amino-2-(2,2-dimethyl-3-hydroxypropoxy)benzonitrile monohydrochloride (1.0 g) and triethylamine (0.6 ml), the title compound (0.87 g) was obtained. melting point: 148-150° C.
Reaction SMILES: [CH:1](N1C2C=CC=CC=2N=N1)=[O:2].[F:12][C:13]1[CH:14]=[C:15]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:22][NH:21][CH2:20]1>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:22][N:21]([CH:1]=[O:2])[CH2:20]1
Reactant: O=Cn1nnc2ccccc21
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C=O)C3)c(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
N-Formylbenzotriazole (115 mg, 0.78 mmol) was added to a stirred suspension of (S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 82, 153 mg, 0.50 mmol) in THF (5 mL) and stirred overnight. The solvent was removed and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 2-5% methanol-chloroform to give the title compound as a white foam. FAB-HRMS: theory 336.1356 (M+1); meas. 336.1357.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])=[CH:25][CH:24]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: COc1ccc(CC=O)cc1
Product: COc1ccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)cc1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (4-Methoxy-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 396; HRMS: calcd for C23H16F3NO2+H+, 396.12059; found (ESI, [M+H]+), 396.1195.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:11]1([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:21][CH:22]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3CCCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 106.3 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (300 mg, 1.89 mmol, 1.00 eq) and 4-cyclohexylphenol (417 mg, 2.37 mmol, 1.25 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (397 mg, 2.87 mmol, 1.52 eq) was added and the reaction mixture was stirred at room temperature for 27 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100 to 1:75) to afford the title compound as colourless solid (600 mg, 2.01 mmol, quant. yield). Rf=0.35 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C17H19N2O3+ [M+H]+ 299.1390. found: 299.1392. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=2.9 Hz, 1H, aromatic H), 8.46 (dd, J=9.1, 2.9 Hz, 1H, aromatic H), 7.31-7.22 (m, 2H, aromatic H), 7.07 (dd, J=8.7, 2.3 Hz, 2H, aromatic H), 7.00 (d, J=9.1 Hz, 1H, aromatic H), 2.58-2.51 (m, 1H, cyclohexyl H), 2.01-1.64 (m, 5H, cyclohexyl H), 1.56-1.10 (m, 5H, cyclohexyl H). 13C NMR (101 MHz, CDCl3) δ 167.18, 150.71, 145.88, 145.17, 140.22, 134.89, 128.30, 121.12, 111.30, 44.08, 34.59, 26.95, 26.19.
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[N:6]([CH2:16][CH3:17])[CH:7]=[C:8]([C:11]([O:13]CC)=O)[C:9](=[O:10])[C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:18][C:5]2[N:6]([CH2:16][CH3:17])[CH:7]=[C:8]([C:11]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:13])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(CC)c2sc(Br)cc2c1=O
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)sc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of ethyl 2-bromo-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Eur. J. Med. Chem. 1987, 22, 139) (0.500 g) and 4-chlorobenzylamine (1.84 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene. The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield a tan solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.379 g (59%) of the title compound as a white, crystalline solid.
Reaction SMILES: [C:1]([N:5]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[NH:22][CH:21]=2)[N:14]=1)[CH2:6][C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([N:5]([CH2:6][C:7]([OH:9])=[O:8])[NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:30])[F:31])[CH:27]=3)[NH:22][CH:21]=2)[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN(Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N(CC(=O)O)Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-[tert-butyl-[[5-fluoro-2-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]amino]acetate, 155a, (0.200 g, 0.440 mmol) in THF (40 mL) was added a solution of lithium hydroxide hydrate (0.074 g, 1.760 mmol) in H2O (4 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture concentrated in vacuo to remove the THF. The remaining aqueous phase was diluted to 8 mL and the solution was used directly in a preparatory HPLC. The product precipicated when the fraction was concentrated on rotavaporator. The solid was filtered and dried in desiccator with P2O5 to afford 120 mg of the desired product: 1H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 12.41 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 8.30 (d, J=3.5 Hz, 2H), 3.97-3.70 (m, 1H), 3.51 (s, 1H), 1.18 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.92 min, (M+H) 427.40
Reaction SMILES: [F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([OH:5])=O.C(Cl)(=O)OCC.CC[N:49](CC)CC.N>C(Cl)Cl>[F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([NH2:49])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(NCC(F)(F)C(=O)O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: NC(=O)C(F)(F)CNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoic acid (60 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 0° C. was added ethyl carbonochloridate (10 uL, 0.1 mmol), followed by NEt3 (0.021 mL, 0.15 mmol) and NH3*H2O (0.1 mL, 2.6 mmol). The reaction mixture was stirred at rt for 30 min, then concentrated under reduced pressure and purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamide as a white solid (12 mg, 21% yield). LCMS: RT=3.85 min [M+H] 576.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[N:4]1.C[Sn](C)(C)[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]2)=[CH:19][C:18]=1[F:34]>>[OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]4)=[CH:19][C:18]=3[F:34])=[CH:10][CH:9]=2)=[N:4]1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: OC[C@H]1COC(c2ccc(Br)cc2)=N1
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(C4=N[C@@H](CO)CO4)cc3)c(F)c2)CO1

Procedure:
The same procedure as in Example 1 was conducted, except for adding 4-(4(S)-hydroxymethyl-4,5-dihydrooxazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][SH:8].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][S:8][S:21][CH2:12][CH3:13]
Reactant: CCN1C(=O)c2ccccc2C1=S
Reactant: Cn1cccc1CS
Product: CCSSCc1cccn1C

Procedure:
Starting from 1-methyl-2-mercaptomethyl-pyrrole and N-ethylthiophthalimide there is obtained (1-methyl-2-pyrrolyl)methyl-ethyl-disulphide.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH2:11]([C:14]1[C:15]([Cl:24])=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[SH:22])[C:17]#[N:18])[CH:12]=[CH2:13]>CC#N>[CH2:11]([C:14]1[C:15]([Cl:24])=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[S:22][CH2:9][CH:8]=[CH2:7])[C:17]#[N:18])[CH:12]=[CH2:13]
Reactant: C=CCc1c(S)c(Br)cc(C#N)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCSc1c(Br)cc(C#N)c(Cl)c1CC=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
In a mixture of crude 3-allyl-5-bromo-2-chloro-4-mercaptobenzonitrile and K2CO3 (1.79 g, 12.9 mmol) in CH3CN (80 mL), allylbromide (1.12 mL, 12.9 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature, and then filtered off. The resulting solution was evaporated and purified by silica gel chromatography to give the desired product 94 (1.1 g, 77.7% overall yield) as a white solid.