Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[OH:14][C:15]1[C:20]2=[N:21][CH:22]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24](=[O:25])[N:19]2[CH:18]=[CH:17][CH:16]=1.P([O-])([O-])(O)=O.[K+].[K+].Br>C(O)(=O)C.CC(CC)=O>[BrH:1].[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:14][C:15]1[C:20]2=[N:21][CH:22]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24](=[O:25])[N:19]2[CH:18]=[CH:17][CH:16]=1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)c1cnc2c(O)cccn2c1=O
Agent: Br
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1COc1cccn2c(=O)c(C(=O)OCC)cnc12

Procedure:
To a solution of 5.0 g of ethyl α-bromo-o-toluate, 4.7 g of 9-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-3-carboxylic acid, ethyl ester, and 200 ml of ethyl methyl ketone is added 3.9 g of anhydrous dipotassium hydrogen phosphate and the mixture stired and heated under reflux for 18 hours. The cooled mixture is filtered, and the filtrate is concentrated in vacuo to give a semi-solid product. To this product, 3.9 g, in 10 ml of acetic acid is added a solution of 0.81 g of hydrogen bromide in 4 ml of glacial acetic acid, dropwise, with agitation. The crystalline product that separates is filtered, washed with anhydrous ether, and recrystallized from acetonitrile to give the named product.
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[C:2]#N.[BH4-].[Na+].Br[CH2:13][C:14](C)([CH3:18])[C:15]([OH:17])=[O:16].C(N(C(C)C)CC)(C)C>CO.O>[NH2:9][C:7]1[S:8][C:4]([S:1][CH2:2][C:14]([CH3:18])([CH3:13])[C:15]([OH:17])=[O:16])=[CH:5][N:6]=1
Reactant: N#CSc1cnc(N)s1
Reactant: CC(C)(CBr)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(CSc1cnc(N)s1)C(=O)O
Reaction time: 0.5 h

Procedure:
5-thiocyanato-thiazol-2-ylamine (15.7 g) was dissolved in degassed methanol and sodium borohydride (4.5 g) in MeOH was added in one portion. The reaction was stirred for 30 min and 3-bromo-2,2-dimethyl-propionic acid (27 g) (prepared in the same manner as described by Greene at al, J Am Chem Soc 1955, 77, 3016) and diisopropylethylamine (17 mL) was added and the reaction stirred overnight at room temperature. The reaction was diluted with water, partially concentrated in vacuo and 5% citric acid was added until pH 4. The brown precipitate was filtered, washed with water and acetonitrile, and dried over night at room temperature to give 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid as light brown crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:16])[CH:15]=1)[CH3:9])=[O:6].[O:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32]>>[Cl:16][C:14]1[CH:15]=[C:10]([CH:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([NH:32][C:28]3[O:27][CH:31]=[CH:30][N:29]=3)[N:25]=[C:24]([CH3:26])[CH:23]=2)[CH3:9])[CH:11]=[N:12][C:13]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20]
Reactant: Nc1ncco1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(Br)n1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(Nc2ncco2)n1

Procedure:
The title compound is prepared from 2-bromo-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-methylisonicotinamide (25 mg, 0.06 mmol, Step-1, single enantiomer) and oxazol-2-amine (16 mg, 0.19 mmol) according to the procedure similar to that described in Step-4 of Example 445.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[Pt]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Reactant: [H][H]
Agent: [Pt]
Solvent: CN(C)C=O
Product: Nc1cc(OCc2ccccc2)ccc1O
Reaction time: 12 h

Procedure:
50 g. 4-benzyloxy-2-nitrophenol [U.S. Pat. No. 4,603,2091] (Compound XXII) is dissolved in 100 mL dimethylformamide to give a yellow solution which is shaken in the presence of 5% platinum on charcoal under 40 psi pressure of hydrogen. After 12 hours, the reduction is colorless and is filtered through diatomaceous earth to remove the catalyst. The clear filtrate is diluted to 800 mL with ethyl acetate and is washed three times with 500 mL water. The organic layer is evaporated to yield a clear oil, which is triturated with cold methanol and filtered to give 4-benzyloxy-2-aminophenol as a gray solid (Compound XXIII).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Zn+])=[CH:13][CH:12]=1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Brc1cccc(Br)n1
Agent: [Br-]
Product: Fc1ccc(Cc2cccc(Br)n2)cc1

Procedure:
Prepared according to the procedure described in Example 53, Step 2, using 2,6-dibromo-pyridine and 4-fluoro-benzylzinc bromide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49](O)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:52].[OH-].[Na+]>C1C=CC=CC=1>[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1)=[O:52]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: OCc1ccncc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
4-Pyridinemethanol (0.253 g, 2.32 mmol), triphenylphosphine (0.609 g, 2.32 mmol) and diethylazodicarboxylate (0.404 g, 2.32 mmol) were added to a benzene solution of N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.500 g, 1.16 mmol) and the solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous 2N sodium hydroxide solution (15 ml) and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to obtain the titled compound (0.380 g, 0.728 mmol, 63%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]3[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[CH2:6]1)=[O:4].[CH3:33][NH:34][CH3:35]>C(O)C>[Cl:31][C:27]1[C:26]([F:32])=[C:25]([CH:30]=[CH:29][CH:28]=1)[NH:24][C:15]1[C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH:7]3[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:34]([CH3:35])[CH3:33])[CH2:6]3)[CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Reactant: CNC
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (470 mg, 0.98 mmol) was treated with a 33% solution of dimethylamine in ethanol (20 ml) and stirred at room temperature for 3 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (9/1). The fractions containing the expected product were combined and evaporated under vacuum. The residue was re-columned eluting with methylene chloride/methanol (saturated with ammonia) (92/8). The fractions containing the expected product were combined and evaporated to give the title product (185 mg, 39%); 1H NMR Spectrum: (DMSO d6 at 100° C.) 1.40-1.65 (m, 1H); 1.75-1.95 (m, 2H); 2.00-2.30 (m, 7H); 3.05 (dd, 2H); 3.40-3.62 (m, 2H); 3.62-3.75 (m, 1H); 3.88 (dd, 1H); 3.95 (s, 3H); 4.45-4.65 (m, 1H); 7.15-7.30 (m, 2H); 7.30-7.47 (m, 1H); 7.50-7.7 (m, 1H); 7.88 (s, 1H); 8.40 (s, 1H); 9.25 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: COc1ccccc1
Product: COc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and anisole.
Reaction SMILES: O[C:2]1([CH3:13])[CH:7]([CH3:8])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][C:3]1([CH3:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][C:3]([CH3:12])([CH3:11])[C:2]=1[CH3:13]
Reactant: CC1C(C)(C)CCC(C)(C)C1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1=C(C)C(C)(C)CCC1(C)C
Yield: 89.9 %

Procedure:
25.9 g of 1-hydroxy-1,2,2,5,5,6-hexamethylcyclohexane are dissolved in 600 ml of benzene and, after the addition of a spatula tip of p-toluenesulphonic acid, held at boiling temperature on a water separator for 3 hours. The mixture is cooled, treated with sodium carbonate, stirred briefly, filtered and the benzene is distilled off at normal pressure. Distillation of the residue gives 21 g of 1,2,3,3,6,6-hexamethyl-1-cyclohexene as a colourless liquid of boiling point 65°-67° C./10 mm Hg.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1.C(OCC)(=O)C>CS(C)=O>[O:14]1[C:15]2[C:22]3[CH2:23][CH2:24][O:25][C:21]=3[CH:20]=[CH:19][C:16]=2[O:17][CH2:18][CH:13]1[CH2:12][N:26]1[CH2:27][CH:28]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCO4)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)CCO4)C1
Temperature: 25 °C

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3,8,9-tetrahydrofuro[3,2-f]-[1,4]benzodioxin-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 4 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform to give 0.32 g of the (S)-enantiomer of the title compound as a gold solid, m.p. 207-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([N+:11]([O-])=O)=[CH:5][C:4]=1[CH3:14]>C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([NH2:11])=[C:7]([CH3:10])[C:8]=1[CH3:9]
Reactant: COc1c(C)cc([N+](=O)[O-])c(C)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(C)cc(N)c(C)c1C

Procedure:
2-Methoxy-1,3,4-trimethyl-5-nitrobenzene (2.3 g) from the step above, was dissolved in 250 mL ethylacetate, to which Pd/C (0.6 g) was added. House vacuum was applied to it and then it was flushed with hydrogen. This cycle was repeated three times. The suspension was kept at room temperature with a hydrogen balloon overnight. The suspension was then filtered through a pad of Celite® and evaporated to dryness. Elution on a silicagel column (DCM: EtOAc, 10:1-5:1) gave 4-methoxy-2,3,5-trimethylaniline as a solid with slight pink color (0.9 g). 1H-NMR (300 MHz, CDCl3), δ=6.4 (s, 1H), 3.631 (s, 3H), 3.392 (br s, 2H), 2.202 (s, 6H), 2.046 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=149.73, 140.35, 129.85, 128.36, 119.92, 115.17, 60.33, 16.02, 13.24, 12.83 ppm.
Reaction SMILES: P(OC)(OC)OC.C(N(CC)CC)C.[CH2:15]1[CH2:43][O:42][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C:28](=[O:41])[C:29](=[CH:39]O)[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:16]1>C(O)(C)C.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[CH2:43]1[CH2:15][O:16][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C:28](=[O:41])[C@H:29]([CH3:39])[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:42]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC(=O)C(=CO)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: COP(OC)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)CC1=O
Yield: 6.7 %

Procedure:
A solution of chloroiridic acid (30 mg.) and trimethyl phosphite (4.5 ml.) in aqueous 90% isopropanol (60 ml.) was heated under reflux for 17 hr. The solution was then neutralised with triethylamine and 20,20-ethylenedioxy 2-hydroxymethylene-5α-pregnane-3,11-dione (2 g.) was added. The mixture was heated under reflux for 40 hr. then cooled and partitioned between water and methylene chloride. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue (1.94 g.) was subjected to preparative t.l.c. giving two fractions. The less polar fraction (0.18 g.) was crystallised from methanol to give 20,20-ethylenedioxy-2α-methyl-5α-pregnane-3,11-dione (0.13 g.), m.p. 179°-180°, [α]D + 77.5°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:19]=[C:18]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Ni]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:19]=[C:18]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:17]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(OCCCCOCc2ccccc2)nc1NC(=O)C(C)(C)C
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCCCCOCc2ccccc2)nc1NC(=O)C(C)(C)C
Yield: 71.4 %

Procedure:
Intermediate 8 (2.46 g, 5.4 mmol) was hydrogenated under an atmosphere of H2 (40 psi) using Raney Ni (1.59 g, 27.1 mmol) in THF (120 mL). The reaction was filtered to remove the Raney Ni and the filtrate was concentrated to afford ethyl 3-(6-(4-(benzyloxy)butoxy)-2-pivalamidopyridin-3-yl)propanoate (intermediate 9) (1.76 g, 71.5% crude) as an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1(C)[O:23]C(=O)[CH2:20][C:18](=O)[O:17]1.CN(C1C=CC=CN=1)C.ClC(OC(C)=C)=O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[CH2:18]([O:17][C:16](=[O:23])[CH2:15][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:20]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CCCOCc1ccccc1
Agent: C=C(C)OC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Benzyloxybutyric acid (6.38 mL), Meldrum's acid (5.76 g) and dimethylaminopyridine (9.77 g) were dissolved in DCM (200 mL) and cooled to 0° C. A solution of isopropenyl chloroformate in dichloromethane (100 mL) was added dropwise and stirring at 0° C. continued for a further 2 h. Potassium hydrogen sulphate (200 mL of a 10% aqueous solution) was then added, the organic phase separated, dried over sodium sulphate, and evaporated under reduced pressure. The residue was dissolved in ethanol (200 mL) and heated at reflux overnight. Following cooling, the solvent was evaporated under reduced pressure and the resultant oil was purified by flash silica column chromatography. 6-Benzyloxy-3-oxo-hexanoic acid ethyl ester was isolated as an orange oil (8.53 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>C1COCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:18]#[N:19])=[C:7]2[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCO
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2-methoxy-ethanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 6-iodo-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 355 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:5]=[N:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[N:7]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: N#Cc1cccc(CNc2cncc(Cl)n2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 3-[(6-chloro-pyrazin-2-ylamino)-methyl]-benzonitrile I-4n (37.6 mg, 0.154 mmol), piperazine (16 mg, 0.185 mmol), sodium t-butoxide (18 mg, 0.185 mmol), BINAP (3.8 mg, 0.006 mmol), and Pd2(dba)3 (2.8 mg, 0.003 mmol) in toluene (2 mL) was heated at reflux under nitrogen for 10 h. The solution was cooled to room temperature and filtered through a celite pad. The celite pad was washed with ethyl acetate several times. The combined filtrate was concentrated in vacuo to give the crude title compound 4-S. The product was purified by chromatography (silica, 10% MeOH/dichlormethane with 1% NH4OH) to give the title compound 4-S (10 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[CH2:2][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:21]2)=[CH:37][CH:38]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (338 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (715 mg, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([N:16]2[CH2:28][CH2:27][C:19]3([CH2:23][N:22]([C:24](=[O:26])[CH3:25])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[C:9]=1[Cl:29])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]([N:22]1[CH2:21][CH2:20][C:19]2([CH2:18][CH2:17][N:16]([C:10]3[CH:11]=[C:12]([CH:13]=[C:8]([NH2:7])[C:9]=3[Cl:29])[C:14]#[N:15])[CH2:28][CH2:27]2)[CH2:23]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC2(CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC2(CCN(c3cc(C#N)cc(N)c3Cl)CC2)C1
Yield: 91 %

Procedure:
tert-butyl(3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)carbamate (100 mg, 0.231 mmol) in DCM (2 mL) was treated with TFA (0.338 mL, 4.39 mmol) at room temperature for 2 h. Solvent was evaporated and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0-5% methanol/dichloromethane). 3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-5-amino-4-chlorobenzonitrile (70 mg) was obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.C1(C)C=CC=CC=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 490.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenylamine (0.07 g, 0.29 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (0.22 g, 1.3 mmol, 4.5 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was precipitated from methanol to give N-({[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide as a white solid (0.6 g, 50% yield). 1H NMR (400 MHz, DMSO): 12.49 (s, 1H), 12.35 (s, 1H), 12.82 (s, 1H), 8.32 (s, 1H), 7.89 (dd, 1H), 7.53 (t, 1H), 7.42 (d, 2H), 7.34 (d, 4H), 7.29 (m, 1H), 7.19 (d, 1H), 6.64 (d, 1H), 3.82 (s, 2H); MS (ESI) for C21H16FN5O2S: 422 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (4 g, 26.5 mmol) and NaOH 1M (52.9 ml, 52.9 mmol) in THF (60 ml), methanesulfonyl chloride (2.474 ml, 31.8 mmol) was slowly added and the reaction was stirred at RT overnight. The mixture was acidified and extracted twice with EtOAc; the combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The resulting solid was suspended in MeOH (120 ml) and stirred overnight. The precipitate was collected by filtration to give 4-(methylsulfonamidomethyl)-benzoic acid (1.99 g, 8.68 mmol, 32.8% yield, MS/ESI+ 229.9 [MH]+).