Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25](I)[CH2:26][CH3:27].C(N(C(C)C)[CH:32]([CH3:34])[CH3:33])C>CN1CCCN(C)C1=O>[CH2:25]([N:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:33][CH2:32][CH3:34])[CH2:26][CH3:27]
Reactant: CCCI
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 38 %

Procedure:
6.9 g (21.4 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at 80° overnight and at 100° for 2 hours with 7.65 g (45 mmol) of propyl iodide in 80 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 6.5 g ([50 mmol) of N-ethyldiisopropylamine. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 3.32 g (38%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 208°-210°.
Reaction SMILES: [NH3:1].S(=O)(=O)(O)O.[O:7]=[P:8]12[O:19][P:17]3([O:20][P:10]([O:12][P:13]([O:16]3)([O:15]1)=[O:14])(=[O:11])[O:9]2)=[O:18]>O>[P:8]([OH:19])([O-:15])([O-:9])=[O:7].[NH4+:1].[NH4+:1].[O:11]=[P:10]12[O:9][P:8]3([O:15][P:13]([O:16][P:17]([O:19]3)([O:20]1)=[O:18])(=[O:14])[O:12]2)=[O:7]
Reactant: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=P([O-])([O-])O
Product: [NH4+]

Procedure:
Anhydrous ammonia and sulfuric acid were also added. The ratios of P2O5, NH3 and H2SO4 were about 100:11.26:3.84. Reaction of the materials yielded a diammonium phosphate product with an analysis of 18.1% nitrogen, 46.4% P2O5, and 1.2% free water after drying. This analysis meets requirements for both U.S. and foreign sale as fertilizer grade diammonium phosphate.
Reaction SMILES: Cl[C:2]1C=CC(N)=NC=1C.[N:10]1([C:15]2[N:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH:14]=[N:13][N:12]=[N:11]1>>[CH3:2][C:19]1[C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[C:15]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:20]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Reactant: Cc1nc(N)ccc1Cl
Product: Cc1nc(-n2cnnn2)ccc1CC(=O)O

Procedure:
The title compound was prepared from 5-chloro-6-methylpyridin-2-amine in six steps in an analogous fashion to that described for the synthesis of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (Method 1, Steps A-F): LC-MS (IE, m/z): 192 [M+1-N2]+, 220 [M+1]+; 1H-NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.9 (d, 1H), 7.85 (d, 1H), 3.79 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[N:7]=[C:8]([C:11](=[O:13])[CH3:12])[S:9][CH:10]=1>O1CCCC1>[CH3:5][C:6]1[N:7]=[C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])[S:9][CH:10]=1
Reactant: CC(=O)c1nc(C)cs1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a stirred solution of ethynylmagnesium bromide (0.5 M in THF, 30.6 mL, 15.30 mmol) maintained under nitrogen at −20° C. was added slowly a solution of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one (1.8 g, 10.20 mmol, 80%) in tetrahydrofuran (10 mL) over a period of 20 min. The resulting solution was stirred for 3 hr at 20-30° C. and then quenched by the addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/6) to yield 0.5 g (26%) of the title compound as a yellow solid: LC-MS: m/z=+168 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of 1-BOC-4-formyl-piperidine (210 mg) in dry 1,2-dichloroethane (10 mL), was added morpholine (86 mg) and glacial acetic acid (60 μL) and stirred for 1 h at room temperature. To the mixture was added sodium triacetoxyborohydride (272 mg) and the mixture stirred for 12 h. The reaction mixture was extracted into DCM (25 mL), washed with 50% sodium bicarbonate solution (10 mL), brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash chromatography to give 4-morpholine-4-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg). Treatment with TFA yielded the desired amine which was isolated as the TFA salt.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][N:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:36][C:28]1[CH:29]=[C:30]([N:4]2[C:5]3[C:10](=[C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[N:3]2)[CH:31]=[CH:32][C:27]=1[O:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Cc1n[nH]c2cccc(OCc3ccccc3)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nn(-c2ccc(OCc3ccccc3)c(F)c2)c2cccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
A mixture of 3-methyl-4-[(phenylmethyl)oxy]-1H-indazole (D30) (0.952 g, 4 mmol), 4-benzyloxy-3-fluorobenzeneboronic acid (1.97 g, 8.0 mmol), copper (II) acetate (1.09 g, 6.0 mmol), pyridine (0.647 mL, 8.0 mmol) and powdered 4A molecular sieves (4 g) in dichloromethane (25 mL) was stirred in an air atmosphere at room temperature. After 48 hrs, the mixture was filtered through Celite, concentrated, redissolved in ethyl acetate, refiltered and concentrated and then chromatographed (0-50% ethyl acetate in hexane and 0-40% diethyl ether in hexane). A white solid crystallised out from some fractions and this was collected by filtration to give the title compound (D31) (0.45 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:19][N:18]=[C:17]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[S:16]2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:39]([N:46]1C=CN=C1)(N1C=CN=C1)=[S:40].[NH2:51]N>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]([C:39]([NH:46][NH2:51])=[S:40])[N:18]=[C:17]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[S:16]2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC1(c2cccc(O[Si](C)(C)C(C)(C)C)c2)NN=C(c2cc(F)ccc2F)S1
Reactant: NN
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC1(c2cccc(O[Si](C)(C)C(C)(C)C)c2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (0.845 g, 1.50 mmol) was weighed into a 25 mL flask and suspended in 10 mL of anhydrous THF, followed by addition of thiocarbonyldiimidazole (0.294 g, 1.65 mmol). The reaction mixture was then heated to reflux for 3 hours. The reaction was cooled to room temperature, and then hydrazine (0.235 mL 7.50 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated, and the residue was loaded onto Biotage (flash column chromatography 10-50% ethyl acetate/hexanes) to provide 143 mg (80% purity) of the desired product.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[C:9]([Si:13]([CH3:23])([CH3:22])[O:14][CH2:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:9]([Si:13]([O:14][CH2:15][CH2:16][C:17]1[S:18][C:19]([Cl:8])=[CH:20][CH:21]=1)([CH3:23])[CH3:22])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Cl)s1

Procedure:
NCS (0.826 g) was added portionwise to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane [WO 2008096129] (1.5 g) in chloroform (50 mL) and the resulting mixture was heated at reflux for 3 days. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL), then dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with isohexane to give the subtitled compound as a clear oil. Yield 1.00 g.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(#N)C.[Cl:12][CH2:13][CH2:14][CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2.[I-].[K+]>O>[ClH:12].[CH:27]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:16]([CH2:15][CH2:14][CH2:13][N:5]3[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Reactant: OCC1CCCNC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cl
Product: OCC1CCCN(CCCN2c3ccccc3CCc3ccccc32)C1
Yield: 61 %

Procedure:
A mixture of 3-(hydroxymethyl)piperidine (1.01 g, 0.0088 mol), acetonitrile (9 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.86 g, 0.003 mol, pre-pared similarly as described in example 1) and potassium iodide (0.56 g, 0.003 mol) was heated at reflux temperature for 18 h. Water (20 ml) was added, and the mixture was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was redissolved in a mixture of water (20 ml) and concentrated hydrochloric acid (3 ml), and extracted with dichloromethane (3×10 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from a mixture of methanol (0.5 ml) and ethyl acetate (5 ml), affording 0.8 g (61%) of the title compound as needles.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([O-])=[O:8].[CH3:14][O:15][CH2:16][CH2:17][N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O.Cl>>[CH2:12]([O:11][C:5]([C:6]1[C:7](=[O:8])[N:18]([CH2:17][CH2:16][O:15][CH3:14])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COCCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
50 ml. of NaOEt (0.5 g. Na--0.021 mole) was added to 3.4 g. (0.021 mole) of ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution was achieved and then 3.2 g. (0.011 mole) of 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and this mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the ensuing precipitate filtered off and rinsed with water. Recrystallization from ethyl acetate gave 3.5 g. of the title product--m.p. 178°-179° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Br:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].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>CN(C=O)C>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.141 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.029 g, 0.141 mmol), HATU (0.064 g, 0.169 mmol) and DIPEA (0.029 mL, 0.169 mmol) in DMF (1 mL) was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative LCMS (acetonitrile:water with 0.1% formic acid) to give the title compound (15 mg, 19.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (br. s., 1H), 7.77 (s, 1H), 7.57 (d, 1H), 7.45 (s, 1H), 7.40 (d, 1H), 7.25 (t, 1H), 4.18-4.59 (m, 2H), 2.21 (s, 3H). ES MS: m/z 541, 543.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][C@H:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C@@H:24]([NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (125 mg, 0.34 mmol), (R)-2-amino-3,3-dimethyl-1-pyrrolidin-1-yl-butan-1-one hydrochloride (155 mg, 0.70 mmol), EDC (148 mg, 0.77 mmol) and HOBt (104 mg, 0.772 mmol). DMF (4.0 mL) was added followed by i-Pr2NEt (0.19 mL, 1.07 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was taken up in EtOAc and 10% citric acid and the organic layer washed with 10% citric acid, sat. NaHCO3, sat LiCl and brine, dried over MgSO4, and concentrated to give 162 mg (90%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a viscous brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cu][C:10]#[N:11]>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dibromopyridine (20.0 g, 84.4 mmol) was dissolved in dimethylformamide (422 mL). To the stirred solution was added copper(I) cyanide. After refluxing for 5 h, the mixture was cooled to room temperature and stored overnight. The reaction mixture was diluted with ethyl acetate (1200 mL) and filtered through a Buchner funnel containing sand, Celite, and silica gel layers. The filtrate was concentrated to a volume of 400 mL. This organic liquid was diluted with water (300 mL) and the resulting liquid was extracted with ethyl acetate (2×200 mL). The organic extracts were combined, washed with water (2×300 mL) and brine (1×250 mL), and dried over magnesium sulfate. After concentration, the product was purified via silica gel chromatography (50:50 ethyl acetate/CH2Cl2) to afford the title compound (9.79 g).
Reaction SMILES: CC(N(C)C)=O.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:14])=[O:13].[NH2:21][C@@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29]2[N:38]=[C:37]([N:39]([CH2:42]C)[CH2:40]C)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH2:24][CH2:23]1>C(Cl)Cl>[ClH:14].[CH3:40][N:39]([CH3:42])[C:37]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([NH:28][C@@H:25]2[CH2:26][CH2:27][C@H:22]([NH:21][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9][C:8]([F:20])([F:19])[F:7])[CH2:23][CH2:24]2)[N:38]=1
Reactant: CCN(CC)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NC(=O)c3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of polymer supported DMA (2.45 g, 7.35 mmol) in CH2Cl2 (6 mL) were added 2-trifluoromethoxy-benzoyl chloride (472 mg, 2.10 mmol) and cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethylquiazoline-2,4-diamine obtained in step C of example 9 (300 mg, 1.05 mmol). The mixture was stirred at ambient temperature for 24 h, filtered, poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 25% EtOAc in hexane), and concentrated. To a solution of the residue in EtOAc (1 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The reaction mixture was stirred at ambient temperature for 1 hr, and concentrated. A solution of the residue in Et2O (10 mL) was stirred at ambient temperature for 1 hr and the precipitate was collected by filtration to give cis-N-[4-(4-dimethylaminoquinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamide hydrochloride (145 mg, 27%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[C:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34](C)C(N3CCCC3)[CH2:32][CH2:31]4)=[N:24][CH:25]=2)=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[C:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]([S:9]([CH3:8])(=[O:11])=[O:10])[CH:2]([CH2:1][N:3]3[CH2:6][CH2:7][CH2:5][CH2:4]3)[CH2:32][CH2:31]4)=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1N1CCCC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1CN1CCCC1
Temperature: 25 °C

Procedure:
0.13 mL (0.93 mmol) triethylamine and 36 μL (0.47 mmol) methanesulphonic acid chloride are added successively at 0° C. to a solution of 200 mg (0.47 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-yl methyl-1,2,3,4-tetrahydro-quinoline (see Example 3.46) in 5 mL DCM. The reaction mixture is heated to RT and stirred for a further hour at this temperature. Another 36 μL (0.47 mmol) methanesulphonic acid chloride are added and the mixture is stirred for a further hour at RT. The reaction mixture is poured onto water and exhaustively extracted with DCM. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NN3CCOCC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture is microwave at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.[CH3:31][O:32][NH2:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][O:32][CH3:31])=[O:18])=[N:14][CH:15]=1
Reactant: CON
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CONC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.5 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (96 mg, 0.228 mmol) obtained in Example 12 in methylene chloride (3 ml), O-methylhydroxyamine hydrochloride (23 mg, 0.273 mmol), 1-hydroxybenzotriazole (31 mg, 0.228 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.273 mmol) and 4-methylmorpholine (59 μl, 0.546 mmol) were added. The reaction solution was stirred for 5 days at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 65% ethyl acetate/hexane was concentrated under reduced pressure to obtain a white solid. The resulting solid was washed with ethylacetate-hexane, and then was collected by filtration, to obtain the title compound (66 mg, 0.147 mmol, 64%) as a white powder.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:17]1[CH:21]2[CH2:22][C:23](=[O:24])[CH:19]([CH2:20]2)[CH2:18]1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[OH:24][C:23]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH2:22][CH:21]2[CH2:20][CH:19]1[CH2:18][CH2:17]2
Reactant: O=C1CC2CCC1C2
Reactant: COC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2(O)CC3CCC2C3)cc1
Temperature: -47 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-iodobenzoate (23.1 g, 0.0882 mol) dissolved in anhydrous THF (200 mL) was cooled to −47° C. Isopropyl magnesium chloride (48 mL of a 2.0 M solution in THF, 0.097 mol) was slowly added to the solution. The reaction mixture was stirred at −47° C. for 1 h, then cannulated into a pre-cooled solution of norcamphor (11.6 g, 0.105 mol) in THF (100 mL) at −47° C. The reaction mixture was subsequently stirred at −40° C. overnight, and was then allowed to warm to −20° C. Saturated aqueous ammonium chloride was added. EtOAc was used to extract three times. The combined organic portion was washed with water and brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (gradient elution; 0%-30% EtOAc/hexanes as eluent) to afford the title compound.