Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:14]2[CH:13]=[CH:12][C:11]([C:25]3[CH:30]=[N:29][C:28]([NH2:31])=[N:27][CH:26]=3)=[C:10]([F:9])[CH:15]=2)=[N:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1cnc(Br)cn1
Product: Nc1cnc(-c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 838 using 5-bromopyrazin-2-amine in Step A and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine in Step B. MS (ESI): mass calcd. for C20H15FN6, 358.13; m/z found, 359.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.50-8.44 (d, J=1.4, 2H), 7.95-7.90 (d, J=1.5, 1H), 7.63-7.55 (m, 2H), 7.52-7.44 (m, 3H), 7.43-7.38 (m, 1H), 7.06-7.03 (m, 1H), 7.03-7.01 (dd, J=6.2, 1.6, 1H).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cu][C:12]#[N:13].[OH-].[NH4+]>CN(C=O)C>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([C:12]#[N:13])=[C:3]([Cl:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(F)c(Br)c(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cc(N)cc1Cl
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A mixture of 4-bromo-3-chloro-5-fluoroaniline (2.08 g, 9.27 mmol) and copper(I)cyanide (0.83 g, 9.27 mmol) in DMF (15 ml) was heated in microwave reactor at 190° C. for 1 h. Reaction mixture was poured into 12% ammonium hydroxide (200 ml) and stirred for 30 min. Thus formed precipitate was filtered, washed with water and dried in vacuum to obtain 1.21 g (77%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (dd, 1H), 6.60 (m, 1H), 6.86 (bs, 2H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH2:14][O:13]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]>ClCCl>[CH3:1][NH:2][CH2:14][CH:12]([C:6]1[CH:5]=[C:4]([F:3])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1)[OH:13]
Reactant: Fc1cc(C2CO2)cc(F)c1F
Reactant: CN
Solvent: ClCCl
Product: CNCC(O)c1cc(F)c(F)c(F)c1
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a solution of methylamine (20 mL, 2.0 M in methanol, 40 mmol) was added 2-(3,4,5-trifluorophenyl)oxirane (0.17 g, 0.98 mmol) at room temperature. The reaction mixture was stirred at that temperature for 24 hours. Solvent and excessive methylamine were evaporated, leaving a solid. The solid was dissolved in dichloromethane (5 mL). To the resulting clear solution was added hexanes (15 mL), standing overnight. The solid precipitant was collected by filtration to yield the title compound (0.14 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[C:10]([C:17]([OH:19])=O)=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:14]4[CH2:15][CH2:16]4)[CH:13]=3)[C:17](=[O:19])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cn(C3CC3)nc2C(=O)O)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2C(=O)c3nn(C4CC4)cc3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-1H-pyrazole-3-carboxylic acid (Step 39.2). tR: 3.88 min (HPLC 1); tR: 0.88 min (LC-MS 2); ESI-MS: 395 [M+H]+ (LC-MS 2); Rf=0.33 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.04 (m, 2H) 1.08-1.14 (m, 2H) 1.90 (s, 3H) 3.34 (s, 3H) 3.83-3.91 (m, 1H) 6.11 (s, 1H) 7.18-7.23 (m, 2H) 7.30-7.38 (m, 3H) 7.68-7.71 (m, 1H) 7.88 (s, 1H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:18][CH2:19][C:20](C)(C)N=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)[OH:25]>C(O)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:18][CH2:19][CH3:20])=[O:25])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)COC(c2ccc(C3CCC4(CC3)OCCO4)cc2)=N1
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCC(=O)CC2)cc1

Procedure:
3 g of the product of step (iii) (9.51 mmol) are dissolved in 60 ml of ethanol and 4.0 ml of 96% sulphuric acid are added, and the mixture is refluxed for 22 hours. The solvent is partially evaporated off and the remaining mixture is taken up with a mixture of 300 ml of a saturated sodium bicarbonate solution and 150 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried and, after filtration, the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a silica gel column, eluting with an 8/2 hexane-ethyl acetate mixture. The compound of the title is obtained in the form of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[F:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:39][C:38]=1[F:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 4.77 mmol), (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol), Cu(OAc)2(1.301 g, 7.16 mmol), triethylamine (3.33 mL, 23.87 mmol) and powdered 3 Å molecular sieves (2 g) in CH2Cl2 (60 mL) was stirred in a flask open to the air and equipped with a drying tube. After 12 hours the mixture was treated with additional (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol) and Cu(OAc)2(1.301 g, 7.16 mmol) and stirred at room temperature for 4 d. The mixture was diluted with CH2Cl2, filtered through Celite and the dark brown filtrate was concentrated to dryness. The crude material was purified by flash chromatography on silica gel (0-4% EtOAc/CH2Cl2) to afford the desired compound which was further purified by flash chromatography on silica gel eluted (0-40% EtOAc/hexane) to give the desired compound as a light-tan solid (406 mg, 14%). LCMS (m/z, ES+)=619 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[C:23]4[CH2:22][C:21]([O:24]CC)=[CH:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC1CC2C(NC3O[C:43]([C:46]4[CH:51]=CC(C(F)(F)F)=CC=4)=[CH:44][N:45]=3)=CC=CC=2CC=1)C>>[N:45]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][C:11]([NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]5[C:23]=4[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]5)=[N:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:44][CH2:43][CH2:46][CH2:51]1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccc(N5CCCC5)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 7B for the product of Example 1H.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>>[CH2:1]([O:8][CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:19][NH2:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1ccc(Cl)c(COCc2ccccc2)n1
Solvent: O
Product: NNc1ccc(Cl)c(COCc2ccccc2)n1
Temperature: 120 °C

Procedure:
A sealable flask is charged with 2-(benzyloxymethyl)-3,6-dichloropyridine as prepared in Step 2 (950 mg, 3.5 mmol), hydrazine hydrate (1 mL) is added, and the reaction is heated to 120° C. overnight. After cooling the solids are collected by filtration to provide 2-(benzyloxymethyl)-3-chloro-6-hydrazinylpyridine.
Reaction SMILES: [CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1
Reactant: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1)[C@H]2O5
Reactant: BrCC1CC1
Solvent: O
Product: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5

Procedure:
In an illustrative embodiment, a mixture of norbuprenorphine, a mild base, and cyclopropylmethyl bromide are heated in an oilbath at about 80-100° C. until the reaction is substantially complete. The reaction mixture is then added over 5 minutes to 160 ml of water, with mechanical stirring, yielding a gum. The mixture is stirred and filtered, and the filter cake is washed with water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, and then boiled in alcohol, cooled, and filtered to yield buprenorphine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH2:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[Cl-].[NH4+].CC(C)=O>[Zn].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[S:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(Sc2cc(N)c([N+](=O)[O-])cc2Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(Sc2cc(N)c(N)cc2Cl)c1

Procedure:
To an ice bath cooled solution (0° C.) of 4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine (2.30 g, 7.80 mmol), ammonium chloride (6.26 g, 117 mmol), acetone (32.5 mL), and water (6.5 mL) was added portion-wise zinc powder (5.10 g, 78.0 mmol). The reaction mixture was removed from the ice bath and after 30 min, the reaction mixture was filtered through a pad of Celite® and washed with EtOAc. The filtrate was placed in a sep funnel and the organic layer was collected. The organic layers dried, filtered, and concentrated under reduced pressure. The crude material was used without further purification in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[O:13][C:12]2[CH:14]=[C:15]([F:21])[C:16]([S:18]([OH:20])=[O:19])=[CH:17][C:11]=2[O:10]1.[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[O:13][C:12]2[CH:14]=[C:15]([F:21])[C:16]([S:18]([Cl:30])(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(O)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Reaction time: 0.67 h

Procedure:
To a solution of 2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5 sulfinic acid (3.2 g, 7 mmol) in chloroform (25 mL) was added N-chlorosuccinimide (1.0 g, 7 mmol, 1.0 eq.) at 20° C. After 40 min, the reaction mixture was filtered and the filtrate was evaporated. The residue was suspended in dichloromethane, dried over sodium sulfate and the solvent was removed in vacuo, affording the title product as a light yellow gum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].[CH2:11](Cl)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14].O>CN(C=O)C>[CH3:14][C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:12][CH2:11][CH:2]([O:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCC(C)=CCC(OC(CC=C(C)CCC=C(C)C)c1ccccn1)c1ccccn1
Reaction time: 8 h

Procedure:
To a mixture of 18.6 g. (0.20 moles) 2-hydroxymethylpyridine in dry DMF is added, in small portions, 8.8 g. of sodium hydride (60% in oil), and the mixture is stirred for one hour at 60° C. Then 34.6 g. (0.2 moles) geranylchloride is added and the reaction mixture is stirred overnight at 50°-60° C. 200 ml. of water is added to the reaction mixture, which then is extracted with ethyl ether. After separation the organic layer is washed with a 10% KOH solution and then with water until neutral. The extract is dried over anhydrous Na2SO4, and the solvent is removed in vacuo. The yield was 36.5 g. of the crude ether, which was purified on silica gel as described below. The actual compound have nD24 : 1.5048.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[K+]>CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][N:16]=[C:10]([OH:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#Cc1ccc(I)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc(-c2ccc(I)cc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of ethyl 3-(4-iodophenyl)propiolate (420 mg, 1.39 mmol) in MeOH (10 mL), were added hydroxylamine hydrochloride (391 mg, 5.20 mmol) and KOH (5 M in methanol, 1.7 mL, 8.5 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was redissolved in water (15 mL) and acidified with 2 M aqueous HCl to pH 2˜3. The precipitate was collected by filtration to afford the title compound (228 mg, 57%). 1H NMR (DMSO-d6, 400 MHz): δ 11.51 (brs, 1H), 7.94 (d, 2H), 7.65 (d, 2H), 6.67 (s, 1H).
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[C:33]([C:34](Cl)=[O:35])=[C:32]([CH3:37])[O:31][N:30]=1>ClCCl>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:34]([C:33]2[C:29]([C:23]3[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[N:30][O:31][C:32]=2[CH3:37])=[O:35])[N:10]=1)[CH3:20]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCOC(=O)Cc1cccc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)n1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Add Et3N (0.7 ml, 5.06 mmol) to a solution of ethyl 2-(2-Aminopyridin-6-yl)acetate (for preparation see Goto, Jiro; Sakane, Kazuo; Nakai, Yoshiharu; Teraji, Tsutomu; Kamiya, Takashi. J. Antibiot. (1984), 37(5), 532–45) (0.6 g, 3.33 mmol) and 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (0.694 g, 2.53 mmol) in dichloromethane (7 ml) and stir overnight. Dilute the reaction with dichloromethane, wash (H2O then brine), dry (MgSO4), filter, and concentrate. Column chromatography (silica gel, hexanes/EtOAc gradient) gives the title compound (0.81 g, 77%). Mass Spectrum (FIA) (m/z) 418.2 [M+1]
Reaction SMILES: Br[CH:2]=[C:3]([CH3:5])[CH3:4].[Mg].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:14].[Cl-].[NH4+]>O1CCCC1>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)([OH:14])[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: COc1ccccc1C(=O)c1ccccn1
Reactant: CC(C)=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(C=C(C)C)c1ccccn1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
43.84 g of 1-bromo-2-methylprop-1-ene in 150 ml of tetrahydrofuran were added dropwise to 9.8 g of magnesium in 50 ml of tetrahydrofuran while heating at reflux. After 1 hour the mixture was allowed to cool to room temperature, whereupon 47.7 g of 2-methoxyphenyl 2-pyridyl ketone in 200 ml of tetrahydrofuran were added slowly. After stirring for 2 hours at room temperature 200 ml of saturated ammonium chloride were added and the mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:6) followed by ethyl acetate/petroleum ethyl (1:4) for the elution to yield 36.6 g of 1-(2-methoxyphenyl)-3-methyl-1-(2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][C:19]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([O:30][CH2:31][C:32](O)=[O:33])[CH:25]=3)=[N:18][C:17]=2[N:16]([CH2:35][CH2:36][CH3:37])[C:14]1=[O:15])[CH2:11][CH3:12]>>[CH3:37][CH2:36][CH2:35][N:16]1[C:14](=[O:15])[N:13]([CH2:10][CH2:11][CH3:12])[C:22](=[O:23])[C:21]2[C:17]1=[N:18][C:19]([N:20]=2)=[C:24]1[N:28]([CH3:29])[NH:27][C:26]([O:30][CH2:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:33])=[CH:25]1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)Nc3ccc(Cl)c(Cl)c3)NN1C)N=2

Procedure:
Using 3,4-dichloroaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [C:1](C=P(CCCC)(CCCC)CCCC)#N.[C:17]([C:19]1[CH:50]=[CH:49][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:33][CH:32]3[O:34][CH:28]([CH2:29][N:30]([CH2:35][CH2:36][NH:37][S:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])(=[O:40])=[O:39])[CH2:31]3)[CH2:27]2)=[C:21]([F:51])[CH:20]=1)#[N:18].C1COCC1>CO>[C:17]([C:19]1[CH:50]=[CH:49][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:33][CH:32]3[O:34][CH:28]([CH2:29][N:30]([CH2:35][CH2:36][N:37]([CH3:1])[S:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])(=[O:40])=[O:39])[CH2:31]3)[CH2:27]2)=[C:21]([F:51])[CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(OCCN2CC3CN(CCNS(=O)(=O)c4ccc(F)cc4F)CC(C2)O3)c(F)c1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2)S(=O)(=O)c1ccc(F)cc1F
Temperature: 160 °C
Yield: 52.4 %

Procedure:
Cyanomethylenetri-n-butylphosphorane (90%, 0.158 g, 0.59 mmol) was weighed into a microwave vial. N-(2-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-2,4-difluoro-benzenesulfonamide (100 mg, 0.2 mmol, from example 11 above) and THF (2 mL) were added. Methanol (16 μl, 0.39 mmol) was then added and the reaction was heated with microwave irradiation at 160° C. for 15 min. MeOH (1 mL) was added and the reaction was heated with microwave irradiation for a further 10 min in order to consume excess reagent. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent. The product isolated could be purified further by recrystallisation from MeOH to give a solid (55 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1)=[O:9]
Reactant: Nc1nc(C(F)(F)F)c(-c2ccccc2)s1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(C(F)(F)F)c(-c2ccccc2)s1)c1cc(Br)ccc1O
Yield: 33.2 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].CI.[C:19](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:10][CH3:19])[CH2:8][O:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(N)ccc2c1OCC(=S)N2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(N)ccc2c1OCC(SC)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 7-amino-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate (Intermediate 29, 0.795 g), methyl iodide (0.710 g) and potassium carbonate (1.38 g) in acetone (20 mL) was stirred at room temperature for 2 hours. The resultant mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give methyl 7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate (0.648 g) as a sandy coloured solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH:27][C:37](=[O:38])[CH2:36][Br:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (25.0 g, 66.58 mmol, 1.0 equiv; example 1/step 4) in dichloromethane (250 mL) at 0° C. were slowly added triethylamine (16.84 g, 166.46 mol, 2.5 equiv) and bromoacetyl chloride (20.96 g, 133.17 mol, 2.0 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 2 h at rt. The reaction mixture was cooled again to 0° C., diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over Na2SO4, concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with hexane/ethyl acetate (65:35) to obtain 23.1 g (70%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.40 (s, 9H), 2.92 (br s, 2H), 3.62 (hr s, 1H), 4.03 (d, J=7.1, 2H), 4.30 (s, 2H), 4.72 (d, J=5.1, 2H), 5.24 (dd, J=10.5 Hz, J=1.0, 1H), 5.35 (dd, J=16.6 H, J=0.7, 1H), 5.50 (d, J=7.7 Hz, 1H), 5.98-6.05 (m, 1H), 6.82(d, J=8.8 Hz, 1H), 7.68 (dd, J=8.6 Hz, J=1.5 Hz, 1H), 7.73 (d, J=1.3 Hz, 1H), 9.43 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from N-(2-amino-ethyl)-acetamide and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 142-155° C.; LC-MS: 457 (MH+); HPLC RT: 3.35 minutes.