Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.[NH2:20][N:21]1[C:25](=[O:26])[CH2:24][NH:23][C:22]1=[S:27]>>[BrH:1].[C:11]([C:9]1[CH:10]=[C:5]([C:3]2[CH2:2][S:27][C:22]3=[N:23][CH2:24][C:25](=[O:26])[N:21]3[N:20]=2)[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: NN1C(=O)CNC1=S
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Product: Br
Product: CC(C)(C)c1cc(C2=NN3C(=O)CN=C3SC2)cc(C(C)(C)C)c1O

Procedure:
34.4 g (0.11 mol) of 2-bromo-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone from Example 1(a) and 13.8 g (0.11 mol) of 1-amino-2-thioxo-5-imidazolidinone from step (a) were heated at 90° C. for 30 minutes in 300 ml of glacial acelic acid. After cooling, the precipitate was filtered off and washed with 250 ml of ethyl acetate, and the crystals were dried in vacuo over phosphorus pentoxide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:16][C:17]#[N:18].[NH4+].[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>CC(C)=O.CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]([C:17]2[S:16][C:2]3[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:18]=2)[CH3:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CNc1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1ccc2c(=O)nc(N(C)c3ccc(Cl)cc3)sc2n1
Yield: 39.2 %

Procedure:
The reaction procedure of Example 57 was followed except that 2.175 g (12.68 mmol) of 2-chloro-6-methylnicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 1.01 g of ammonium thiocyanate, 15 ml of acetone, 1.81 g of N-methyl-4-chloroaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 1.58 g of 2-[N-(4-chlorophenyl)-N-methylamino)-7-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].N1CCCCC1>CO>[CH:1](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:13])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC=O
Solvent: C1CCNCC1
Solvent: CO
Product: CC=C1C(=O)Nc2ccccc21

Procedure:
0.85 mL (15 mmol) acetaldehyde were added dropwise to 2.0 g (15 mmol) indolin-2-one and 0.20 mL piperidine in 20 mL methanol. The reaction mixture was refluxed for 3 h and then evaporated down. The residue was triturated in diisopropylether and suction filtered.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br-].[CH2:7]([N:11]([CH3:42])[C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])[CH2:8][CH2:9][CH3:10].C([O:50][C:51]1[CH:68]=[CH:67][C:66]2[C:65]3[CH2:64][CH2:63][C@@:61]4([CH3:62])[C:57](=[CH:58][CH2:59][C@@H:60]4[OH:69])[C:56]=3C(C=O)=C[C:53]=2[CH:52]=1)C1C=CC=CC=1>CCCCCC.CS(C)=O.O1CCCC1>[CH2:1]([O:50][C:51]1[CH:68]=[CH:67][C:66]2[C:65]3[CH2:64][CH2:63][C@@:61]4([CH3:62])[C:57](=[CH:58][CH2:59][C@@H:60]4[OH:69])[C:56]=3[C:14]([CH:15]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:12]([N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH3:42])=[O:13])=[CH:12][C:53]=2[CH:52]=1)[C:2]1[CH:9]=[CH:8][CH:7]=[CH:4][CH:3]=1
Reactant: CCCCN(C)C(=O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Reactant: C[C@]12CCc3c(c(C=O)cc4cc(OCc5ccccc5)ccc34)C1=CC[C@@H]2O
Agent: [Br-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(C)C(=O)CCCCCCCCC=Cc1cc2cc(OCc3ccccc3)ccc2c2c1C1=CC[C@H](O)[C@@]1(C)CC2
Reaction time: 1 h

Procedure:
Butyl-lithium (0.8 ml. of a 1.6 molar solution in hexane) was added dropwise to a stirred solution of [9-(N-n-butyl-N-methylcarbamoyl)nonyl]triphenylphosphonium bromide (1.2 g.) in a mixture of dimethyl sulphoxide (2 ml.) and tetrahydrofuran (18 ml.), a solution of 3-benzyloxy-17β-hydroxyoestra-1,3,5(10),6,8(9),14(15)-hexaene-7-carboxaldehyde (0.05 g.) in tetrahydrofuran (2 ml.) was then added and the mixture was stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure. Water (15 ml.) was added and the mixture was extracted three times with ethyl acetate (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and acetone as eluant. There was thus obtained as an oil 11-(3-benzyloxy-17β-hydroxyoestra-1,3,5(10),6,8(9),14(15)-hexaen-7-yl)-N-n-butyl-N-methylundec-10-enamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)=[O:17]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1cccc(Cl)c1)c1cc(Br)ccc1OCc1cccc(Cl)c1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
3-Chlorobenzyl bromide (568 mg, 2.76 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 ml) over 1 min. The reaction mixture was stirred at 56° C. for 24 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as an off white solid. 427 mg.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:22]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:42].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C@H:9]([C@@H:22]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([NH:13][C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[C:11]([OH:42])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N[C@H](CO)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OCc1ccccc1)c1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@@H](N[C@H](C(=O)O)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,3S,4S)-3,4,5-tris(benzyloxy)-2-(((R)-1-phenylethyl)amino)pentan-1-ol (110 mg, 0.209 mmol) in acetone (2 mL, 0.1 M) was added Jones reagent (0.21 mL, 0.522 mmol, 2.5 M solution in H2O) at 0° C. The reaction mixture was stirred for 4 hrs at 0° C., quenched with isopropyl alcohol and filtered through a pad of celite and washed with CH2Cl2. The reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with brine, dried over MgSO4, filtered through a pad of celite, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (1/2) to CH2Cl2/MeOH (20/1) to afford the title product. Yield: 59 mg (0.11 mmol, 52%); white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1.[CH3:18][O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:27]3)[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccc(F)cc2Nc2sccc21
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 40 h
Yield: 25 %

Procedure:
Combine 6-fluoro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.20 g, 4.45 mmol), (S)-2(2-methoxy-ethyl)-piperazine (1.60 g, 11.12 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 40 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 400.4 mg (25%) of a tan foam: mass spectrum (ion spray): m/z 361.1 (M+1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.Cl>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:16][CH:17]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 27.5 g (0.25 mol) of hydroquinone, 11.2 g (0.2 mol) of potassium hydroxide in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 30 g (0.2 mol) of 5-chloro-2,3-difluoropyridine in 200 ml of dimethylsulfoxide is added dropwise thereto. The reaction mixture is then heated to 70° and stirred at that temperature for 4 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is taken up in a hexane/ethyl acetate 2:1 solvent and passed over a silocagel column for purification. After concentrating the eluate, the residue crystallizes to yield 33 g of white crystals, melting at 97°-98°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH2:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-(Benzylcarbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester (0.85 g, 2.50 mmol) was dissolved in HCl/dioxane(10 mL, 4.0 M). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure to provide the desired product in quantitative yield.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:42][CH:43]=[C:44]([CH3:46])[N:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1nc(C)cs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: Cc1csc(C(=O)c2nc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)n1

Procedure:
Starting material: (2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N,4-dimethylthiazole-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CS(C)=[O:26]>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[OH:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(C)=O
Reactant: Fc1ccc(C(c2ccncc2)c2ccc(F)c(F)c2)cc1F
Agent: [Na+]
Agent: [OH-]
Product: OC(c1ccncc1)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Yield: 79.9 %

Procedure:
A solution of 5.66 g (0.0179 mole) of 4-[bis(3,4-difluorophenyl)methyl]pyridine and 12 drops of 50% NaOH in 50 ml of DMSO was stirred at room temperature for 4.5 h with air bubbling through the reaction mixture. Water was added to the solution, and a tan precipitate was collected. This was recrystallized from CH2Cl2 -hexane to give 4.75 g (79.9%) of the title compound as a white, crystalline solid, mp 147°-149° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 4.3 h
Yield: 62.8 %

Procedure:
The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2 mL) and ethanol (2 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 4.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl yielding a solid. The solid was collected by filtration and was recrystallized from ethanol-water to yield a white solid(0.14 g, 64%): mp 269.8–270.8° C. 1H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.88 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.23 (d, 1H, J=8.6 Hz), 5.98 (q, 1H, J=7.0 Hz). FABLRMS m/z 347 (M−H). ESHRMS m/z 347.0560 (M−H, Calc'd 347.0531). Anal. Calc'd for C18H11F3O4: C, 62.08; H, 3.18. Found: C, 61.48; H, 3.22.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2].C(O)C.[BH4-].[Na+].C(O)(=O)C>O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2]
Reactant: CCCCCC(=O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Reaction time: 0.25 h

Procedure:
To 2 g. 9β-hydroxy-15-oxo-12-prostenoic acid ethyl ester, dissolved in 20 ml. dry ethanol, is added with ice cooling under nitrogen with exclusion of moisture and stirring, portionwise over 15 minutes, 206 mg. NaBH4. The mixture is stirred 15 minutes more and 0.325 ml. glacial acetic acid is added dropwise thereto. The mixture is poured into 50 ml. of water. Solvent is removed by distillation and the residue is extracted three times with 15 ml. amounts of diethyl ether. The organic phase is washed with water and dried over Na2SO4. Solvent is removed to obtain as residue 9β,15-dihydroxy-12-prostenoic acid ethyl ester which, after chromatographic purification twice (first silica gel/dichloromethane:acetone = 10:1; then silica gel/petroleum ether:ethanol = 9:1), can be separated into the two 15-epimers:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(S)cc1
Reactant: COC(=O)C=CC=CCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.50 g, 7.3 mmol) and 4-methoxythiophenol (0.93 mL, 7.3 mmol) in tetrahydrofuran (40 mL) was added dropwise triethylamine (1.1 mL, 8.0 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for one hour, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (50 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography ((9:1 to 8:2 40-60° C. petroleum ether:diethyl ether) to give the title compound as a colourless oil (1.6 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:28].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C1COCC1.C(OC(=O)C)C>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[NH:28]
Reactant: N
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 50 h
Yield: 89 %

Procedure:
Part B: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (19.0 g, 0.057 mol) is dissolved in benzene (150 mL) and PCl5 (13.0 g, 1.1 molar equivalent) is added. The resulting mixture is heated at reflux temperature for two hours, allowed to attain room temperature and concentrated in vacuo to give a residue. The residue is dissolved in anhydrous THF, cooled to 0° C. and transferred into an autoclave. Excess NH3 is quickly added from a lecture bottle and the mixture is stirred at room temperature for 50 hours. A mixture of ethylacetate and aqueous NaHCO3 is added. The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/1 (v/v), silicagel) to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzene-carboxamidine (16.9 g, 89% yield). Melting point: 108–109° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O.CN(C=O)C>CC(=O)OCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429 mmol) in sulfurous dichloride (5 mL, 0.429 mmol) was added DMF (3.32 μL, 0.043 mmol). The resulting mixture was stirred at 60° C. After 2 h, TLC analysis (PE/EA=1/1) showed the starting material had disappeared. The solvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.416 mmol, 97% yield). A solution of 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.437 mmol) in THF (5 mL) was added to ammonium hydroxide (10 mL, 257 mmol). The resulting mixture was stirred at 0° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried and concentrated to give a white solid of 2-(4-bromo-2-fluorophenyl)acetamide (100 mg, 0.280 mmol, 63.9% yield), which was used into the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J=8.2 Hz, 1H), 3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43](=[O:46])[CH2:44][NH2:45])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:46])[CH3:44])([CH3:41])([CH3:40])[CH3:39].[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:45])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)Cl)s1
Reactant: CC(C)(C)OC(=O)CN
Product: CC(=O)OC(C)(C)C
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Yield: 20 %

Procedure:
Using a procedure analogous to Example 134E, 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride and 2-amino-acetic acid tert-butyl ester (787 mg, 6 mmol) give the title compound (670 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH3:20])[N:18]=[CH:19][C:12]=12.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH3:20])[N:18]=[CH:19][C:12]=12
Reactant: Cc1ccc(N)cc1C#Cc1cncc2c1cnn2C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1C#Cc1cncc2c1cnn2C

Procedure:
In analogy to GP 5, 200 mg of 4-methyl-3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-ylethynyl)-phenylamine (Intermediate 3.2, 0.4 mmol, 1 eq.) were treated with 47 μL phenyl isocyanate (0.44 mmol, 1.1 eq.) in 4 mL DCM at rt. Aqueous work-up followed by HPLC purification provided the target compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12](Cl)Cl.S(Cl)(Cl)=O>CO>[C:1]1([C:7]#[C:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]#[C:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Agent: O=C(O)C#Cc1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C#Cc1ccccc1
Reaction time: 8 h

Procedure:
Phenylpropiolic acid was synthesized according to the method as described in J. Chem. Soc., Vol. 83, page 1154. To a mixture of 42 g of phenylpropiolic acid and 50 ml of methylene chloride was added 42 ml of thionyl chloride, and the mixture was mildly refluxed by heating on a water bath. After the completion of the generation of gas, the solvent and excessive thionyl chloride were distilled off under reduced pressure. The pale yellow liquid thus obtained was gradually added to 300 ml of methanol under cooling with ice. After being allowing to stand overnight, the solvent was distilled off under a reduced pressure, and the residual liquid was washed with water and dried to obtain 44.5 g of almost pure methyl phenylpropiolate.