Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([O-:5])=[O:4].FC(F)(F)C([O-])=O.[C:15]1(C)[CH:20]=[CH:19][C:18]([Tl+2])=[CH:17][CH:16]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1[CH:16]=[CH:15][CH:20]=[CH:19][C:2]=1[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])C(F)(F)F
Reactant: Cc1ccc([Tl+2])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
A 75 ml Fisher-Porter tube was charged with 2.5 gms of p-tolyl thallium bis(trifluoroacetate), 10 ml of toluene, 5 ml of trifluoroacetic acid and 5 ml of trifluoroacetic anhydride. The reaction mixture was stirred at room temperature under 84 psig of CO pressure. There was no appreciable uptake of CO nor could any toluic acid be isolated from the reaction product after the workup procedure of Example 1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@:24]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])=[O:30])[CH2:25]2)[CH2:17][CH2:16]1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>ClCCl>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@:24]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[C:35]([O:37][S:56]([CH3:55])(=[O:58])=[O:57])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])=[O:30])[CH2:25]2)[CH2:17][CH2:16]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(O)ccc4OC)C3)CC2)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Treat a stirred solution of 1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-methanone (0.25 g, 0.22 mmol) and dichloromethane (5 mL) at 0° C. with diisopropylethylamine (0.14 mL, 0.84 mmol) and methane sulfonyl chloride (0.04 mL, 0.5 mmol). Stir the reaction mixture at 0° C. for two hours, dilute with dichloromethane and wash with water. Dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the product by column chromatography (silica gel, elute sequentially with 3% methanol in dichloromethane then with 5% methanol in dichloromethane) and concentrate the appropriate fractions to afford 0.19 g of the title compound, Rf=0.28 (silica gel, 5% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods swell known in the art.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)=[O:13]>>[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:22]=[CH:21][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from the product of Example 10 and 4-formylbenzoic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:25][NH2:26]>CCO>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:25][NH2:26])=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 61.3 %

Procedure:
Synthesized according to General Procedure C: 51i (4.00 g, 11.6 mmol, 1.0 equiv.), anhydrous hydrazine (1.5 mL, 46.4 mmol, 4.0 equiv.), EtOH (25 mL, 0.5 M). 46i (2.35 g, 61.4%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.09 (br s, 1H), 7.62 (d, 2H, J=8.0 Hz), 7.45 (d, 2H, J=8.0 Hz), 3.88 (br s, 2H) 3.75 (br s, 2H), 3.35 (br s, 2H), 3.07 (s, 2H), 2.56 (br s, 2H), 2.42 (br s, 2H). 13C-NMR (125 MHz, CDCl3) δ169.8, 168.9, 139.1 131.8 (q, JC-F=32.1 Hz), 127.5, 125.7 (q, JC-F=3.6 Hz), 123.7 (q, JC-F=271.1 Hz), 60.5, 53.7 (br), 53.2 (br), 47.6 (br), 42.2 (br). 19F-NMR (470 MHz, CDCl3) δ
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[CH:35][C:36]=1[OH:37].C(N(C(C)C)CC)(C)C>O>[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:40][CH2:39][CH2:38][C:33]2[CH:34]=[CH:35][C:36]([OH:37])=[C:31]([Cl:30])[CH:32]=2)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(NCc2ccccc2)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1cnc(NCCc2ccc(O)c(Cl)c2)nc1NCc1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To 8 ml NMP solution of 750 mg of 4-benzylamino-2-methylsulfonylpyrimidine-5-carboxamide were added 765 mg of 2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 1.07 ml of diisopropylethylamine, followed by stirring a 110° C. for 1 hour. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia) and the resulting crude crystals were recrystallized (methanol-ethyl acetate) to obtain 280 mg of 4-benzylamino-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [Br:1]Br.II.[C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].O>C(O)(=O)C>[Br:1][CH2:9][C:7](=[O:8])[CH2:6][C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: BrBr
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
Under a nitrogen atmosphere, a solution of bromine (1.16 ml, 22.59 mmol) in 17 ml of acetic acid containing a small crystal of iodine was added over 2.5 hours to a solution of acetoacetanilide (4.0 g, 22.57 mmol) in 12 ml of acetic acid, at room temperature (cooling with cold water). The reaction mixture was stirred at room temperature for 3 hours, then poured into 100 ml of ice-cold water and the crude solid product was filtered off. Following crystallization from ethanol, 3.30 g of 4-bromoacetoacetanilide were obtained, m.p 130°-132° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]2[S:11][C:10]([C:13]([NH:15][C@@H:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[ClH:1].[NH:37]([C:38]([NH:3][C:4]1[C:12]2[S:11][C:10]([C:13]([NH:15][C@@H:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reaction time: 18 h

Procedure:
A solution of 44 mg (0.12 mmol) of 7-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 32.8 μl (0.24 mmol) of triethylamine and 28 mg (0.24 mmol) of phenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 20 mg (36.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[NH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[S:17]([NH:20][C:21]([N:4]1[C:5]([CH3:8])([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]1)=[O:22])(=[O:18])=[O:19]
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Reactant: CC1=NNC(C)(C)C1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=NN(C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)C(C)(C)C1

Procedure:
11.2 g of the 3,5,5-trimethyl-2-pyrazoline obtained according to example I(b) are added dropwise while stirring, cooling in cold water and under a nitrogen blanket to a solution of 25.2 g of the 2,6-dichlorobenzenesulphonylisocyanate obtained according to example I(a) in 200 ml of dry toluene. After stirring at room temperature for two hours, the precipitate is sucked off and washed successively with dry toluene and petroleum ether (40-60). The desired 1-(2,6-dichlorophenylsulphonylcarbamoyl)-3,5,5-trimethyl-2-pyrazoline is obtained in a yield of 20.07 g; melting-point 270° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29].[H-].[Na+].BrC[C:34]([O:36]CC)=[O:35].[OH-].[Na+].O1CCC[CH2:42]1>C(O)C>[CH3:42][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH2:1][C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product of step (d) (20 g) in dry tetrahydrofuran (500 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.43 g) portionwise. The reaction was stirred at 0° C. for 30 minutes then ethyl bromoacetate (8.19 g) was added dropwise and the reaction was allowed to warm to 20° C. and stirred for a further 3 hours. Ethanol (100 mL) was then added and stirring was continued at 20° C. for 30 minutes. Sodium hydroxide solution (2M, 100 mL) was then added and the resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was then partitioned between dichloromethane (700 mL) and water (700 mL). The aqueous layer was acidified to pH 1 by the addition of hydrochloric acid (2M) and then extracted with dichloromethane (3×500 mL). The combined organic layers were dried and the solvent removed in vacuo. Purification by chromatography on silica gel (Biotage), eluting with 10% methanol/1% ammonia (specific gravity 0.880) in dichloromethane gave the title compound as a pale yellow oil (15 g). LC retention time 2.18 mins. Mass spectrum m/z 485 [M+]
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10]CC)=O)=[CH:5][CH:4]=1)#[N:2].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:8]([C:6]1[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:10])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(C#N)s1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(C#N)s1

Procedure:
Prepared from ethyl 5-cyano-2-thiophenecarboxylate [CAS-No. 67808-35-9] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow solid (6.66 g).
Reaction SMILES: [H-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>C1COCC1>[F:26][C:15]([F:14])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:19]2=[N:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a stirred solution of sodium hydride (6.2 g, 156 mmol, 60% dispersion), tosyl chloride (27 g, 141.8 mmol), in anhydrous THF (200 mL) under a nitrogen atmosphere was added a solution of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (26.38 g, 141.8 mmol) in THF (150 mL) dropwise at a rate which maintained the internal temperature of the reaction below 40° C. The reaction mixture was stirred overnight at room temperature and analysis by LCMS showed no starting material remained after this time. The reaction mixture was concentrated to remove most of THF and diluted with DCM and water. The organic layer was separated and the aqueous layer further extracted with DCM. The organic layers are combined and washed with brine, dried over magnesium sulphate and concentrated to a volume which was appropriate to load onto the top of a silica plug (300 mL) pre-wet with DCM, and the silica was washed with 2.5 L DCM. The filtrate was concentrated to give the product as a slightly brown solid (44.1 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:14]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:13][N:12]=[N:11]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)[CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: CO
Solvent: O
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1

Procedure:
A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimidine (1.2 equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilution with water and acidification, the solid formed was filtered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at 60° C. for 2-3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz), 7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H, J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[CH:8]=1.[I-].[K+].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:19]=[C:18]([Cl:27])[C:17]=1[OH:28].[OH-].[K+].[C:31](#N)C>>[Cl:27][C:18]1[CH:19]=[C:20]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:21]=[C:16]([Cl:15])[C:17]=1[O:28][C:2]1[CH:31]=[C:6]([C:7]2[S:11][N:10]=[C:9]([CH3:12])[CH:8]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Cl)cc(C2=NCCO2)cc1Cl
Reactant: CC#N
Reactant: Cc1cc(CCCCCCl)sn1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(-c2cccc(Oc3c(Cl)cc(C4=NCCO4)cc3Cl)c2)sn1

Procedure:
A suspension of 6.5 g 5-(5-chloropentyl)-3-methylisothiazole, 5.3 g potassium iodide, 9.1 g 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol and 3.9 g potassium hydroxide in 300 ml acetonitrile was heated at reflux for 40 hours. Filtration, concentration and flash filtration (silica gel; 1:1 hexane/ethyl acetate) gave 9.8 g of oily product which when crystallized from hexane at Dry Ice temperature gave 5.3 g 2-{3,5-dichloro-4-[(5-(3-methyl-5-isothiazolyl)pentyl)oxy]phenyl}-4,5-dihydro-oxazole as a colorless solid, m.p. 38°-39.5° C.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[O:39])[CH:27]=2)[N:22]=1>C1COCC1.CCOC(C)=O.O>[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)([C:11]3[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=3)[OH:39])[CH:27]=2)[N:22]=1
Reactant: Cn1ccnc1
Reactant: COc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
nBuLi (0.0665 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0665 mol) in THF (60 ml) under N2 flow. The mixture was stirred for 15 minutes. Chlorotriethyl-silane (0.0684 mol) was added dropwise. The mixture was stirred for 15 minutes. nBuli (0.059 mol) was added dropwise. The mixture was stirred for 15 minutes. A solution of intermediate 14 (0.038 mol) in THF (150 ml) was added at −70° C. The mixture was stirred at −70° C. for 1 hour and poured out into water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH 96/4/0.2). The pure fractions were collected and the solvent was evaporated, yielding 11 g (59%) of 2-chloro-4-(3-chlorophenyl)-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (intermediate 15).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCCCCBr
Yield: 95.3 %

Procedure:
A solution of 6-bromohexanoyl chloride (100 g, 468 mmol) in 350 ml of tetrahydrofuran was poured into a solution of diethylamine (1.08 moles, 79 g, 112 ml) in 800 ml of rapidly stirring water. The mixture was then extracted with 2×200 ml of CH2C12 and the pooled extracts were washed with 250 ml of brine. Drying over Na2SO4 and concentration under reduced pressure afforded 111.6 g (446 mmol, 100% yield) of product as a pale yellow oil: 1H NMR (Me2SO-d6, 300 MHz) δ 3.5 (t, J=6.7 Hz, 2 H ), 3.2°-3.3 (m, 4 H ), 2.3 (t, J=7.5 Hz, 2 H ), 1.8 (m, 2 H ), 1.3-1.6 (m, 4 H ), 1.1 (t, J=7.1 Hz, 3 H ), 0.99 (t, J=7.0 Hz, 3 H ).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]([OH:29])=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:33]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:32]C1.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:32][NH:33][C:27]([C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:10])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2cccnc2c(C(=O)O)c1-c1ccccc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccccc2)c(C(C)NC(=O)OC(C)(C)C)nc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1-(tert-butoxycarbonylamino)ethyl)-3-phenyl-1,5-naphthyridine-4-carboxylic acid (205 mg, 0.52 mmol) in DMF (5 mL) was added PyBop (407 mg, 1.5 mmol), methanamine (0.52 mL, 2.0 eq) and N-ethyl-N-isopropyl-propan-2-amine (0.18 mL, 2.0 eq). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between water (10 mL) and EtOAc (15 mL). The water layer was extracted with EtOAc (5 mL×2). The combined organics were washed with water (10 mL×2), 0.5 N NaOH (5 mL×2), water (5 mL×2), brine (5 mL) and dried over sodium sulfate. Removal of solvents followed with column chromatography on silica gel (EtOAc/hexane, up to 2/1) to give a white solid. Mass Spectrum (ESI) m/e=407 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:11])[NH2:10])[CH:6]=[CH:7][CH:8]=1.O.[NH2:13]N.[C:15]([NH:18][CH:19]([CH2:27][CH3:28])[C:20](=O)[C:21](OCC)=[O:22])(=[O:17])[CH3:16]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:21](=[O:22])[C:20]([CH:19]([NH:18][C:15](=[O:17])[CH3:16])[CH2:27][CH3:28])=[N:13][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)c1cccc(Br)c1
Reactant: CCOC(=O)C(=O)C(CC)NC(C)=O
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC(NC(C)=O)c1nnc(-c2cccc(Br)c2)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.02 g (8.6 mmol, 1 equiv.) 3-bromobenzenecarboximidamide hydrochloride (Example 31A) are suspended in 50 ml of ethanol, and 1.47 g (10.2 mmol, 1.2 equiv.) hydrazine hydrate are added. After stirring at room temperature for 1 hour, 2.59 g (13 mmol, 1.5 equiv.) of the compound of Example 2A, dissolved in 10 l of ethanol, are added. The reaction mixture is stirred at 80° C. (bath temperature) for 4 hours and then at room temperature over night. The mixture is evaporated to dryness in vacuo and the product is purified by chromatography (flash or column chromatography or preparative HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:19](O)[CH3:20].C([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[C:10]([O:11][CH2:19][CH3:20])[C:4]=2[CH:3]=1
Reactant: CN1c2ccccc2CC(=O)c2cc(Br)ccc21
Reactant: CCO
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CCOC1=Cc2ccccc2N(C)c2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A suspension of 29.5 g of 2-bromo-5-methyl-10,11-dihydro [5H] dibenzo (b,f) azepine-11-one, 295 ml of ethanol and 29.5 ml of ethyl orthoformate was heated to 70°C and then 1 g of p-toluene sulfonic acid was added thereto in small fractions. The mixture was held at 70°C for 11/2 hours and then 15 ml of triethylamine were added dropwise while still hot and the mixture was then cooled. The product crystallized and the mixture was diluted with 300 ml of distilled water, was stirred at room temperature for 30 minutes and was vacuum filtered. The recovered precipitate was washed with water and dried to obtain 31.8 g of 2-bromo-5-methyl-11-ethoxy [5H] dibenzo (b,f) azepine as pale yellow crystals melting at 131°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.O.[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Scheme IA, step A: 2-bromo-4-fluorophenol (15.0 g, 78.5 mmol) was dissolved in THF (200 mL) and treated with potassium carbonate (13.0 g, 94.2 mmol) and ethyl 2-bromopropionate (11.2 mL, 86.4 mmol). The reaction mixture was heated at reflux for 3 hours. Potassium iodide (0.1 g) was added and the reaction mixture was stirred for an additional 2 hours at reflux. The reaction was then cooled, diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography to provide ethyl 2-(2′-bromo-4′-fluorophenoxy)propionate (19.8 g) as a clear oil.