Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=[CH:8][C:7]=1[F:31])C.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:26]1([N:24]([CH3:25])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=4)[CH:23]=[CH:22][C:21]2=3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)ccc21

Procedure:
Following general procedure J and using [4-(5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 17, 0.025 g, 0.059 mmol), methanol (1 mL), tetrahydrofuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate (0.060 g, 1.43 mmol), the title compound was obtained as a white solid (0.023 g, 95%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C#N)=C([Cl:26])N=1)(C)(C)C.C[Mg+].[Br-].[BH4-].[Na+]>>[C:1]([C:5]1[N:10]=[C:9]([Cl:26])[C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)c1ccc(C(C)(C)C)nc1
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Agent: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Product: CC(N)c1ccc(C(C)(C)C)nc1Cl

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of [1-(6-tert-butylpyridin-3-yl)ethyl]amine starting from 6-tert-butyl-2-chloronicotinonitrile (intermediate 22) (2.0 g, 10.3 mmol), MeMgBr (18 ml, 25.7 mmol) and NaBH4 (970 mg, 25.7 mmol). The resulting material was used crude in the following coupling step. (Yield: 1.76 g, 79%) 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 9 H) 1.39 (d, J=6.64 Hz, 3 H) 4.47 (q, J=6.64 Hz, 1 H) 7.26 (d, J=8.01 Hz, 1 H) 7.78 (d, J=8.01 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:10])=[CH:3][C:2]=1[N:1]1[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(C)c(N)c1
Solvent: CC(=O)O
Product: COc1ccc(C)c(-n2cccc2)c1
Temperature: 25 °C

Procedure:
A solution of 88.4 g (0.64 mole) of 3-amino-4-methylanisole in 1.4 liters of glacial acetic acid is heated to 106° and, at this temperature, 114 g (0.86 mole) of 2,5-dimethoxytetrahydrofuran are added in the course of 30 minutes. The mixture is then immediately cooled to room temperature and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-anisole, b.p. 93°-95°/0.04 torr. Rf (toluene/ethyl acetate=10:1): 0.57.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:11].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:11])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)CN2CCN(Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium carbonate (18.84 g) and water (41.4 ml) was added to a stirring suspension at 0° to 5° C. of 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (32.03 g, described in Example 4) and 1-benzylpiperazine (24 ml) in acetonitrile (90 ml). The suspension was stirred at room temperature for 2.5 hr and evaporated. The residue was dissolved in a mixture of water and chloroform, and the chloroform layer was dried and evaporated. Chromatographic purification on silica gel (700 g) using ethyl acetate-hexane (60:1 to 100:1) gave 32 g of 2-(4-benzyl-1-piperazinyl)-1-(3,4-dimethoxyphenyl)-1-ethanone, nmr(CDCl3) δ2.65, 3.57, 3.74, 3.89, 3.91, 6.81, 7.37 and 7.53.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[C:6]([O:14]COC)=[CH:5][N:4]=1.C(Cl)Cl>O1CCOCC1>[Cl:2][C:3]1[N:4]=[CH:5][C:6]([OH:14])=[C:7]([C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1
Reactant: COCOc1cnc(Cl)cc1-c1ncc[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1cnc(Cl)cc1-c1ncc[nH]1
Reaction time: 2 h

Procedure:
Hydrogen chloride in dioxane (4 M, 40 mL) was added dropwise to a solution of 2.06 g (8.60 mmol) of 2-chloro-4-(1H-imidazol-2-yl)-5-(methoxymethoxy)pyridine in Methylene chloride (40 mL, 600 mmol). The suspension was stirred for 2 hours and filtered. The solid was washed with DCM, ether and dried in vacuum. Yield of 6-chloro-4-(1H-imidazol-2-yl)pyridin-3-ol dihydrochloride 2.31 g (100%). MS (ESI+): 196.2. 1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.42 (s, 2H).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([OH:18])=[O:17])=[CH:12][CH:11]=1>CCO.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:6]2[CH:5]=[C:4]([OH:7])[CH:3]=[CH:2][C:1]=2[OH:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=S(O)c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of benzoquinone (23.5 g, 217 mmol) in 500 ml EtOH was added at RT over 30 min to a solution of 4-fluoro-benzenesulfinic acid (34.8 g, 217 mmol) in EtOH (300 mL) and water (500 mL). The resulting solution was stirred 2 h at RT, then diluted to 4 l with warm water. The solution was cooled to 4° C. for 62 h and crystals formed. The crystalline solid was collected by suction filtration and washed with water (3×500 mlL and hexanes (2×500 mL) and dried to give the title compound of Step B (40.8 g). MS (APCl−) Calc.: 268.0. Found: 267.1 (M−1).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(=O)C.[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][OH:33])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.CCOCC>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH:32]=[O:33])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a suspension of PCC (11.52 g, 53.44 mmol) and sodium acetate (4.38 g, 53.4 mmol) in DCM (60 mL) was added a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanol (10.00 g, 41.09 mmol) in DCM (20 mL). After 4 hours at room temperature, the mixture was diluted with ether and passed though a short column of fluorisil® using ether as an eluent. The eluate was concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 8.32 g (84%) of the desired aldehyde as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 9.76 (t, J=1.5 Hz, 1H), 4.05 (bs, 2H), 2.64 (bt, J=11.7 Hz, 2H), 2.45 (dt, J=7.3, 1.5 Hz, 2H), 1.60 (m, 3H), 1.43 (s, 9H, overlapped with m, 2H), 1.08 (dq, J=12.1, 4.0 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (12.8 mg, 0.032 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 22.5 mg, 0.096 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (30.6 mg, 0.160 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21.6 mg, 0.160 mmol), N-ethyl-N-isopropylpropan-2-amine (41.3 mg, 0.320 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (13.3 mg, 67.5%). LRMS (APCI pos): m/e 617 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([NH:9][C:10]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:16][CH2:17]1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Reactant: BrCc1ccc2ccccc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
4-Benzoylureidopiperidine (1.28 g, 0.005 m), 2-(bromomethyl)naphthalene (1.1 g, 0.005 m) and triethylamine (0.6 g, 0.006 m) in dimethylformamide (25 cm3) were stirred at room temperature for 23 hours. Water was added and the precipitated solid filtered off and washed well with water. The solid was suspended in warm ethanol, acidified with ethanolic HCl and then heated until all the solid had dissolved. The title compound crystallised and was collected as the hydrochloride salt, hemihydrate (1.6 g), m.p. 232°-234° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCCCC1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 78.9 %

Procedure:
Under argon atmosphere, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (50 mg, 0.114 mmol), cyclohex-1-en-1-yl trifluoromethanesulfonate (29a) (27.7 mg, 0.120 mmol) and cesium carbonate (112.2 mg, 0.344 mmol) was dissolved in dry N,N-dimethylformamide (570 μL). The solution was degassed under argon and PdCl2(dppf) (5.6 mg, 0.007 mmol) was added. The reaction was heated and shaken at 100° C., for 6.5 hours. The mixture was filtered through Celite®, rinsed with ethyl acetate and dichloromethane. The solution was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (cyclohexane/ethyl acetate 90/01) to provide the desired product (30 mg, 0.09 mmol, 75%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27])[C@H:12]([C:21]([OH:23])=[O:22])[CH2:11][CH2:10][C:9]3=[O:24].[C:28](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.O>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27])[C@H:12]([C:21]([O:23][CH3:28])=[O:22])[CH2:11][CH2:10][C:9]3=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CC[C@H]3C(=O)O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CCC(=O)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Temperature: 25 °C

Procedure:
(S)-1,3-Dimethyl-2,4,10-trioxo-5-phenyl-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizine-7-carboxylic acid (1.85 g, 5.04 mmol), potassium carbonate (2.088 g, 15.11 mmol) and dimethyl sulfate (1.444 mL, 15.11 mmol) were combined in acetone (50 mL) and water (5 mL). The mixture was heated at reflux for 1.5 hours, then cooled to room temperature and evaporated under vacuum. The residue was partitioned between DCM and water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-80% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[O-])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[CH2:17]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>CCCCCC>[CH2:17]([N:21]([CH2:22][CH2:23][CH2:24][CH3:25])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:11])[CH2:18][CH2:19][CH3:20]
Reactant: O=C([O-])Nc1cccc(Br)c1
Reactant: CCCCNCCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)Nc1cccc(Br)c1

Procedure:
A solution of 1.46 g. of phenyl N-(3-bromophenylcarbamate in 15 ml. of tetrahydrofuran is added to a solution of 1.52 g. of di-n-butylamine in 20 ml. of tetrahydrofuran and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords 1,1-di-(n-butyl)-3-(3-bromophenyl)urea, m.p. 80°-81° C.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]=2)=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=Cc1cccnc1Cl
Reactant: O=C(O)c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
To 2-chloronicotinaldehyde (381 mg, 2.69 mmol), 2-fluoro-5-hydroxybenzoic acid (300 mg, 1.92 mmol) and cesium carbonate (1.25 g, 3.84 mmol) was added DMSO (2.5 mL). The mixture was heated to 80° C. in a sealed tube for 3 hours. The cooled reaction was diluted with water and extracted with EtOAc. The aqueous layer was acidified with TFA (pH˜3) and extracted with EtOAc. This layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with Et2O dried to yield 2-fluoro-5-(3-formylpyridin-2-yloxy)benzoic acid as an off-white solid. MS m/z=262 [M+1]+. Calc'd for C13H8FNO4: 261.21.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[NH:31][C:30]2=[O:40])=[CH:25][C:24]=1[O:41][CH3:42])#[N:22]>C(OCC)(=O)C>[NH2:7][N:31]1[C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][C:34](=[O:35])[N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[C:24]([O:41][CH3:42])[CH:25]=2)[C:30]1=[O:40]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)ccc1C#N
Temperature: 57.5 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
Potassium carbonate (1.0 g) and 2,4-dinitrophenoxyamine (0.8 g) were added to a solution of 3-[4-cyano-3-methoxyphenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (1.1 g) in 15 ml of ethyl acetate. The mixture was subsequently stirred for 15 hours at 55-60° C., whereupon the solids formed were separated off and washed using in each case 30 ml of ethyl acetate and diisopropyl ether. The combined filtrates were washed twice using in each case 25 ml of water, dried over sodium sulfate and then concentrated. After crystallization using 10 ml of diisopropyl ether, 0.6 g of the desired product was obtained. M.p.: >230° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH:39]1[O:43][CH2:42][CH2:41][O:40]1>CN(C)C(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[O:40]1[CH2:41][CH2:42][O:43][CH:39]1[CH2:38][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19]
Reactant: BrCC1OCCO1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CC3OCCO3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.4 %

Procedure:
To a stirred solution of N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1, 44 mg) in N,N-dimethylacetamide (0.8 mL) were added cesium carbonate (45 mg), 2-bromomethyl-1,3-dioxolane (23 mg) and tetrabutylammonium iodide (3 mg). The mixture was stirred for 3 days at r.t. More tetrabutylammonium iodide (3 mg) and 2-bromomethyl-1,3-dioxolane (23 mg) were added and the mixture was stirred for 18 h at r.t. and for 24 h at 50° C. 2-Bromomethyl-1,3-dioxolane (23 mg) was added and the mixture was stirred for 5 h at 100° C. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 9:1 to 1:1) to give N-[1,3]dioxolan-2-ylmethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (34 mg) as a light yellow oil. MS: 578.6 ([M+NH4]+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Br)cn2)CC1
Yield: 64.2 %

Procedure:
Heat 2-fluoro-5-bromopyridine (2.15 g, 12.22 mmol) with 1-methyl-piperazine (3.4 mL, 30.54 mmol) in THF (10 mL) in a microwave reactor at 120° C. for 45 min. Dilute with EtOAc (60 mL), then wash with NaHCO3 (2×30 mL) and brine (20 mL). Dry with Na2SO4, filter, and concentrate to give 2.01 g (64%) of the title compound. MS/ES m/z (79Br) 256 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:24])=[CH:18][C:19](C#N)=[N:20][CH:21]=4)[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.C[Mg]Br.C([O:35][CH2:36][CH3:37])C.C(=O)([O-])O.[Na+]>O1CCCC1.Cl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:24])=[CH:18][C:19]([C:36](=[O:35])[CH3:37])=[N:20][CH:21]=4)[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)CCCCN3c1cnc(C#N)cc1C
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C(C)=O)cc1C
Yield: 81.4 %

Procedure:
Under nitrogen atmosphere to a solution of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-4-methylpyridine-2-carbonitrile (Example 59; 70.0 mg, 0.172 mmol) in tetrahydrofuran (2 mL) was added 3M methylmagnesium bromide solution in diethyl ether (0.115 mL, 0.345 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 30 min, the mixture was diluted with 0.1N hydrochloric acid (5 mL) at 0° C. After the resultant mixture was stirred at room temperature for 30 min, the mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (59.6 mg, 0.140 mmol, 81%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [I-].[Na+].C(C1C=C([C:11]2[CH:23]=[CH:22][C:14]3[NH:15][C:16](=[O:21])[O:17][C:18]([CH3:20])([CH3:19])[C:13]=3[CH:12]=2)C=CC=1)#C.Cl[Si](C)(C)C.Cl.[C:30](#[N:32])[CH3:31]>O.CS(C)=O>[CH3:20][C:18]1([CH3:19])[O:17][C:16](=[O:21])[N:15]([C:11]2[CH:12]=[C:13]([C:18]#[C:31][C:30]#[N:32])[CH:14]=[CH:22][CH:23]=2)[C:14]2[CH:22]=[CH:23][CH:11]=[CH:12][C:13]1=2
Reactant: C#Cc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Reactant: CC#N
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(c2cccc(C#CC#N)c2)c2ccccc21
Temperature: 50 °C
Yield: 4.6 %

Procedure:
To a stirred mixture of DMSO, acetonitrile and water (9 mL/3 mL/0.5 mL) was added at rt under nitrogen cuprous cyanide (0.193 g, 2.2 mmol), sodium iodide (11 mg, 0.072 mmol), and 6-(3-ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.2 g, 0.72 mmol). Chlorotrimethylsilane was then added to the above mixture in a dropwise manner. After addition, the mixture was heated at 50° C. for 72 hours. The reaction mixture was then cooled to rt and treated with 0.5 N aqueous HCl cold solution (50 mL). The precipitate obtained was collected on a filter and washed with water. The solid was purified on a silica gel column (hexane:ethyl acetate/2:1) to give the title compound as an off-white solid (10 mg, 4.6%): mp 212-213° C.; 1H-NMR (CHCl3-d6) δ7.96 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H, J=7.8 Hz), 7.60 (d, 1H, J=7.69 Hz), 7.51 (d, 1H, J=7.77 Hz), 7.45 (dd, 1H, J=8.67, 2.21 Hz), 7.31 (d, 1H, J=1.55 Hz), 6.91 (d, 1H, J=8.19 Hz), 1.8 (s, 6H); MS (EI) m/z 302 ([M+], 30%).