Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[N:19]=[C:18]([F:20])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][NH:15]2.C([O-])([O-])=O.[K+].[K+].Br[CH:28]([CH3:30])[CH3:29].C(Cl)(Cl)Cl>CN(C=O)C.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[N:19]=[C:18]([F:20])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: Cc1cc(C)c(CNc2nc(F)nc3[nH]cnc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(CNc2nc(F)nc3c2ncn3C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4,6-dimethyl-pyridin-3-ylmethyl)-(2-fluoro-9H-purin-6-yl)-amine (0.6 g, 1.9 mmol) in DMF (10 ml) under an argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 1.77 g, 5 eq, 13 mmol) followed by 2-bromopropane (1.8 ml, 10 eq, 19 mmol). The reaction mixture was stirred at RT for 24 h, when TLC (CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (50 ml) and ethyl acetate (50 ml), the aqueous phase was separated and extracted with more EtOAc (2×50 ml). The bulked organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→95:5), to provide the product as a yellow film (0.4 g, 59%). δH (250 MHz, CDCl3) 1.52 [6 H, d, J 7.5 CH(CH3)2] 2.27 (3H, s, CH3), 2.45 (3 H, s, CH3), 4.73-4.62 (3H, m, NHCH2 and CH[CH3]2), 6.91 (1 H, s, ArH), 7.12 (1 H, NH), 7.47 (1 H, s, ArH), 8.32 (1 H, s, ArH); δC (250 MHz, CDCl3) 160.77 (C), 157.89 (C), 157.43 (C), 156.12 (C), 155.79 (C), 149.14 (CH), 137.7 (CH), 128.7 (C), 129.76 (C), 124.83 (CH), 47.2 (CH), 40.14 (CH2), 23.9 (CH3), 22.47 (2×CH3), 18.54 (CH3); m/z 315.3 (M+H)
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][C:11]1[CH:12]=[C:13]([OH:20])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:20][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]

Procedure:
In a similar manner to Example 2, starting material step (b), t-butyl bromoacetate (2.9 ml), 3-methyl-4-nitrophenol (2.5 g), anhydrous potassium carbonate (2.7 g) and acetone (100 ml) were reacted to give t-butyl 3-methyl-4-nitrophenoxyacetate (4.19 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.56 (3H, s), 4.71 (2H, s), 6.94 (1H, dd), 7.03 (1H, d), 8.06 (1H, d); Mass Spectrum m/Z 268 (M+H)+.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1CCCCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCCCCCC1Cc1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclooctanone Compound 1a (2.5 g, 19.8 mmol) in THF (5 mL) was added dropwise to a solution of LiHMDS (23.8 mL, 23.8 mmol) in anhydrous THF (50 mL) at −78° C. under a N2 atmosphere. The mixture was stirred at −78° C. for 60 mins, then 1-bromomethyl-3-chloro-benzene Compound 3a (4.1 g, 19.9 mmol) in anhydrous THF (10 mL) was added dropwise. The mixture was stirred for 5 hrs, while warming to r.t. The reaction was quenched with water (5 mL) and the organic layer was diluted with EtOAc (100 mL), then washed with water and brine. The organic layer was separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude oil which was purified by flash chromatography using 3% EtOAc in hexane to afford 2-(3-chloro-benzyl)-cyclooctanone Compound 3b (4.12 g, 82.6%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[CH:13]=1.[OH-:27].[K+].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>O1CCOCC1.O.CCOC(C)=O.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]>[Cl:11][C:9]1[CH:10]=[C:2]([OH:27])[C:3]2[CH:4]=[N:5][N:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]([F:26])[CH:13]=3)[C:7]=2[CH:8]=1
Reactant: [OH-]
Reactant: Fc1cc(-n2ncc3c(Br)cc(Cl)cc32)ccc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc(Cl)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A solution of 4-bromo-6-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole (D10) (410 mg, 0.95 mmol) and KOH (212 mg, 3.8 mmol) in dioxane (10 mL) and water (10 mL) was sonicated under a flow of argon for 5 minutes after which the bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (24 mg, 0.057 mmol) and Pd2 dba3 (17 mg, 0.019 mmol) were added and it was heated to reflux for 2 hours. The mixture was then cooled to room temperature, diluted with EtOAc and water and the pH was adjusted to circa 7. The phases were separated, the aqueous re-extracted with EtOAc and the combined organics were finally dried over MgSO4. The crude material (450 mg) was purified by flash chromatography (Biotage SP4, 25+M silica column) with a gradient of EtOAc 0 to 50% in hexane to afford 60 mg of desired compound (D11).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14].CC(C)([O-])C.[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:5]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])[CH:6]=1
Reactant: COC(=O)c1cc(Br)c[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
Methyl 4-bromo-1H-pyrrole-2-carboxylate (250 mg, 1.23 mmol) and 2-bromo-1-(4-chloro-phenyl)-ethanone (315 mg, 1.35 mmol) were dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. before potassium tert-butoxide (125 mg, 1.11 mmol) was added to the reaction mixture in small portions. The resulting suspension was allowed to warm to room temperature then stirred for 10 min. The reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried and concentrated in vacuo to give a residue that was purified using flash chromatography (Biotage SP4, 40 g cartridge, 0-15% EtOAc gradient in n-hexanes) to give the target compound methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (244 mg) contaminated with an impurity. The mixture was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:48][C:49]1[C:50]([C@H:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=2)[NH2:56])=[N:51][CH:52]=[CH:53][CH:54]=1.Cl.FC(F)(F)C1C=CC([C@@H](C2C(C(F)(F)F)=CC=CN=2)N)=CC=1>C(Cl)Cl>[F:48][C:49]1[C:50]([C@@H:55]([NH:56][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=2)=[O:13])[C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:59][CH:58]=2)=[N:51][CH:52]=[CH:53][CH:54]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(methoxycarbonyl)picolinic acid (101 mg, 0.558 mmol) in DCM (4 mL) was added HATU (217 mg, 0.571 mmol) and DIPEA (0.20 mL, 1.148 mmol). After stirring for 30 min at rt, the reaction was treated with (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (Intermediate 2) (125 mg, 0.364 mmol). After 16 h, the reaction was concentrated in vacuo and then taken up in THF (3 mL), MeOH (1 mL), and 1M LiOH (1 mL). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo, acidified with 1N HCl and extracted with EtOAc (3×5 mL). The combined EtOAc layers were concentrated in vacuo and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with 0% to 100% EtOAc in hexane, to provide the title compound as an off-white solid. 1H NMR (CDCl3:CD3OD, 300 MHz) δ ppm 9.21 (d, J=1.5 Hz, 1H), 8.47 (d, J=4.7 Hz, 1H), 8.39 (dd, J=8.0, 1.9 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 7.42 (t, J=9.5 Hz, 1H), 7.27-7.32 (m, 1H), 6.63 (s, 1H). MS (ESI pos. ion) m/z: 419.9 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:18]=1)[NH2:17]>>[Br:11][C:12]1[CH:18]=[C:16]([NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1Nc1cccc(Br)c1
Yield: 132.2 %

Procedure:
2-chloro-3-nitropyridine (2.0 g, 12.6 mmol, 1 eq) was reacted with 5-Bromoaniline (4.12 ml, 37.8 mmol, 3 eq) for 20 minutes at 180° C. in a microwave reactor. The product was isolated by column chromatography to provide the title compound as a red solid (4.9 g). [M+H] calc'd for C11H8BrN3O2, 293; found 293.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:32]=[CH:31][NH:30][N:29]=1.C1(C)C=CC=CC=1.CN(C)C=O.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:27][C:28]1[CH:32]=[CH:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[N:29]=1
Reactant: O=C1OC2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccncc21
Reactant: Cc1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)c4cnccc45)CC3)cc2)n1
Temperature: 150 °C

Procedure:
To a solution of 1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (30 mg, 0.00007 mol), 3-methyl-1H-pyrazole (7.15 mg, 0.0000871 mol) in toluene (0.5 mL, 0.005 mol) and N,N-dimethylformamide (0.5 mL, 0.006 mol) were added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg, 0.000014 mol), copper(I) iodide (1 mg, 0.000007 mol), and potassium carbonate (21.1 mg, 0.000152 mol). The mixture was heated at 150 Celsius under microwave for 60 minutes. Then the mixture was cooled down to r.t. and filtered. The filtrate was diluted with methanol, and the desired compound was obtained by reversed phase prep-HPLC. MS (ESI): 415.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:11][C:9]1([CH3:10])[O:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:12])[CH2:8]1
Reactant: CC(C)=CC(=O)c1sccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2sccc2O1

Procedure:
A solution of 3-hydroxy-2-(3-methyl-1-oxo-2-buten-1-yl)thiophene (39.0 g, 0.214 mol) and p-toluenesulfonic acid (3.5 g, 18 mmol) in toluene (400 mL) was heated to reflux for 3.5 d. The resultant solution was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo to give a brown oil, 38.62 g (99%). A portion of the resultant oil was purified for analysis by distillation in a Kugelrohr oven at 145° to 155° C. at 0.35 mm Hg to give the product as an amber oil: IR (neat): 2979, 1664, 1530 and 1442 cm-1 ; MS: m/z 183 (MH+); 1H NMR (CDCl3): δ1.51 (s, 6H); 2.67 (s, 2H); 6.67 (d, J=5.4 Hz, 1H) and 7.60 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([O:5][C:6]1[CH:7]=[C:8]2[S:12][CH:11]=[C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:9]2=[C:18]([C:20](O)=[O:21])[CH:19]=1)=[O:4].[CH3:25][N:26](C=O)[CH3:27].Cl.CNC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:3]([O:5][C:6]1[CH:19]=[C:18]([C:20](=[O:21])[N:26]([CH3:27])[CH3:25])[C:9]2[C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1)(=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1]
Reactant: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C(=O)O)c12
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: O
Product: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C(=O)N(C)C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-((2,2-dimethylpropanoyl)oxy)-3-(2-methoxy-2-oxoethyl)-1-benzothiophene-4-carboxylic acid (145 mg) and DMF (dry) (5 mL) were added dimethylamine hydrochloride (50.6 mg), TEA (0.115 mL) and HATU (236 mg) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (133 mg).
Reaction SMILES: [Na].C(S)C.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1>CN(C)C=O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(O)CC(CC(=O)O)c1ccc(O)cc1
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
To a stirred suspension of 57% sodium hydrideparaffin (6.45 g), in dry dimethylformamide (70 ml) is slowly added ethanethiol (11.89 ml) in dry dimethylformamide (20 ml). After stirring the resultant slurry for 15 minutes, a solution of 3-(4-methoxyphenyl)glutaric acid (3.0 g) in dry dimethylformamide (20 ml) is added. The slurry is heated in a bath at 165°to C. for 5.0 hours and most of the solvent is removed by distillation in vacuo. The residue is diluted with water, acidified with concentrated hydrochloric acid and extracted twice with ether (the extracts are discarded). The solution is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is washed once with brine, dried, and the residue crystallized from chloroform-hexane to afford 2.3g of 3-(4-hydroxyphenyl)glutaric acid, melting point 168-170° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:18]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of 114 g (447 mmol) of tert-butyl (3-bromophenyl)carbamate in 800 ml of DMF are added portionwise 19 g (475 mmol) of sodium hydride (60% in oil) and the reaction medium is stirred until the evolution of gas has ceased. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring is continued for 18 hours. The reaction medium is poured into ice-water and extracted with ethyl acetate. The organic phase is separated out by settling of the phases, dried over magnesium sulfate and evaporated. 115 g of tert-butyl (3-bromophenyl)-N-methylcarbamate are obtained in a yield of 95%.
Reaction SMILES: C(OC(OCC)[C:5]([CH:21]=O)([CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]#[N:7])C.[NH2:26][C:27]([NH2:29])=[NH:28]>C(O)C>[NH2:29][C:27]1[N:28]=[C:6]([NH2:7])[C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:21][N:26]=1
Reactant: N=C(N)N
Reactant: CCOC(OCC)C(C#N)(C=O)Cc1cc(OC)c(OC)c(OC)c1
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reaction time: 8 h
Yield: 67.2 %

Procedure:
α-Diethoxymethyl-α-formyl-β-(3,4,5-trimethoxyphenyl) propionitrile (35.1 g, 0.10 mol) was added to an ethanolic solution of guanidine (from 0.35 mol of guanidine hydrochloride). The mixture was heated at reflux for a total of 6.5 hours during which time enough ethanol was allowed to boil off to bring the reaction temperature up to 85°. The dark solution was allowed to cool and stand overnight. The mixture was filtered, and the solid was washed with cold ethanol and dried to yield crude product (24.4 g, 84.1%). Purification was effected by dissolving the crude product in hot aqueous acetic acid and reprecipitation with concentrated ammonium hydroxide. The precipitate was washed twice with water, once with cold acetone, and dried to yield 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (19.5 g, 67.2%), m.p. 197°-198° C. (identity confirmec by nmr). The acetone was concentrated in vacuo to dryness yielding additional though somewhat less pure trimethoprim (2,5 g, 8.6%, m.p. 194°-196° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@H](/C=C/c2ccc(F)cc2)COC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](CCc2ccc(F)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a stirred solution of (R)-4-[(E)-2-(4-fluoro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.205 g) at r.t. in ethanol (5 ml) under an argon atmosphere was added 10% Pd/C (20 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 3 hrs. The catalyst was filtered off and the filtrate was concentrated to give (R)-4-[2-(4-fluoro-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.195 g) as light brown viscous oil. MS (ISP): 324.5 ([M+H]+))
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-:30].[K+].O>C(O)(C)(C)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:22]([NH2:23])=[O:30])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C#N)cc1C
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C(N)=O)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 6-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-5-methylpyridine-3-carbonitrile (100 mg, 0.245 mmol) and potassium hydroxide (41 mg, 0.735 mmol) in tert-butanol (2 mL) was stirred at 80° C. for 2 hr. After cooling, water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from ethyl acetate/isopropyl ether to afford the title compound (70 mg, 67%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21].N1C=CC=CC=1.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:22]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 55.6 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.0 eq, 0.18 mmol), 1-butanesulphonylchloride (23 μl, 1.0 eq, 0.18 mmol) and pyridine (14 μl, 1.0 eq, 0.18 mmol) were added to DMF (1 ml) and the mixture was stirred for 42 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (35 mg, 0.10 mmol, 57%). LCMS: [M+H]+=347, Rt=1.62 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([N:17]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH3:18])=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH2:19][N:17]([CH3:18])[C:15](=[O:16])[CH2:14][CH:9]([CH2:10][CH2:11][OH:12])[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
3,4-Dichloro-β[2-[[3,5-bis-(trifluoromethyl)phenylmethyl]methylamino]-2-oxoethyl]-benzenepropanoic acid (6.1 g) in EtOAc (75 mL) was treated with carbonyldiimidazole (2.43 g) and N,N-dimethylaminopyridine (150 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (1.8 g) in H2O (30 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (150 mL) and washed with 1N HCl (1×100 mL), sat. NaHCO3 (1×100 mL) and water (1×100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (5.7 g). Mass spectrum (FAB): 502.0791.