Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].[CH3:16][C@H:17](O)[CH2:18][CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C@@H:17]([CH2:18][CH3:19])[CH3:16])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: CC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(O[C@H](C)CC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (700 mg, 3.33 mmol) in DCM (40 ml) were successively added (S)-butan-2-ol (0.37 ml, 4.0 mmol), supported PPh3 (loading of 1.52 mmol/g, 4.38 g, 6.66 mmol) and DTAD (1.15 g, 5.0 mmol). The reaction mixture was shaken at RT for 3 h, then filtered and the resin was washed with DCM. The filtrate was evaporated to dryness and the resulting residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→1:1) to yield the title compound (818 mg, 3.07 mmol, 92%) as a colorless oil. TLC: RF=0.85 (heptane/DCM/TBME 1:1:2); HPLC: BtRet=2.46 min; API-MS: m/z 267.2 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.00 (t, J=7.5, 3H), 1.28 (t, J=7.1, 3H), 1.33 (d, J=6.1, 3H), 1.60-1.70 (m, 1H), 1.77-1.89 (m, 1H), 3.56 (s, 2H), 3.86 (s, 3H), 4.17 (q, J=7.1, 2H), 4.25 (sxt, J=6.1, 1H), 6.79 (dd, J=8.3, 2.0, 1H), 6.83-6.87 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[CH2:6]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCCC.CCOC(C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:14](=[O:15])[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCNC
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C#CCN(C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of N-methylprop-2-yn-1-amine (3.05 ml, 36.2 mmol) in THF (50 ml) and NaHCO3 sat. aqueous solution (50.0 ml), N-(benzyloxycarbonyloxy)succinimide (11.31 ml, 39.8 mmol) was added and the reaction was stirred overnight. Then, organic layers were extracted with ethyl acetate (2×100 mL). Organic phases were collected, dried, filtered and solvent was removed under reduced pressure. The product was purified by Biotage Si 10 g with a gradient of heptane and EtOAc affording the title compound (5 g, 24.60 mmol, 68.0% yield) as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:22])([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)[CH:14]=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:26])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)([CH3:22])[CH2:14][N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC1(F)CNC1
Reactant: Cc1nc(C(C)(C=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(C)(CN2CC(F)(F)C2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
To a solution of 5-cyclopropyl-N-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 128a, 0.075 g, 188 μmol) in dichloromethane (1 ml) was added 3,3-difluoroazetidine hydrochloride (26.8 mg, 207 μmol) and triethylamine (21.0 mg, 28.9 μl, 207 μmol). The reaction mixture was sonicated to completely dissolve solids and reaction mixture was then stirred at room temperature for 30 minutes, followed by addition of sodium triacetoxyborohydride (59.9 mg, 282 μmol). The reaction mixture was then stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (9.2 mg, 10%). MS (ESI, m/z): 476.5 (M+H+).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.C(N(CC)CC)C>ClCCl>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[N:13][CH:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:14]
Reactant: O=Cc1ccccn1
Reactant: CC(C)CC(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(N=Cc1ccccn1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-methylpentanoic acid tert-butyl ester hydrochloride (5.00 g, 22.35 mmol), pyridine-2-carboxaldehyde (2.12 mL, 22.35 mmol) and triethylamine (3.11 mL, 22.35 mmol) in dichloromethane (75 mL) was heated under reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool to room temperature, washed with water and brine, dried over MgSO4 and evaporated to give the title compound as an oil.
Reaction SMILES: C(S[C:4]1N=C[C:7]([C:10]([Cl:12])=[O:11])=[C:6]([Cl:13])[N:5]=1)C.C(SC1NC(=O)C(C(O)=O)=CN=1)C.P(Cl)(Cl)(Cl)=O.OC1C(C(O)=O)=NC2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:13][C:6]1[C:7]([C:10]([Cl:12])=[O:11])=[N:34][C:35]2[C:4](=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:5]=1
Reactant: CCSc1ncc(C(=O)Cl)c(Cl)n1
Reactant: O=C(O)c1nc2ccccc2nc1O
Agent: CCSc1ncc(C(=O)O)c(=O)[nH]1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1nc2ccccc2nc1Cl

Procedure:
o-Halogeno-(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention, and processes for their preparation, are known. Thus, for example, J. Am. Chem. Soc. 40,233 (1908) describes the preparation of 2-ethylmercapto-6-chloropyrimidine-5-carboxylic acid chloride by reacting 2-ethylmercapto-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid with phosphorus oxychloride. The reaction of 2-hydroxy-quinoxaline-3-carboxylic acid with thionyl chloride in the presence of a catalytic amount of dimethylformamide to give 2-chloroquinoxaline-3-carboxylic acid chloride is described in Arch. Pharm. 306, 401 (1973). The reaction of 4-chloronicotinic acid with thionyl chloride under reflux to give 4-chloronicotinic acid chloride is described in J. Chem. Soc. (C), 1966, 1816.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[CH2:27][C@@H:26]1[CH2:34][C:35]([O:37][CH3:38])=[O:36]>C(N(CC)CC)C.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[C:33][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH2:27][C@@H:26]1[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C#CCN1CC[C@@H](CCCc2ccnc3ccc(OC)cc23)[C@@H](CC(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
0.35 cm3 of 1-bromo-3,5-difluorobenzene and then 0.112 g of tetrakis(triphenylphosphine)palladium and 0.037 g of cuprous iodide were added at a temperature in the region of 20° C., under an inert atmosphere, to a stirred mixture of 0.77 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-acetate in 7.7 cm3 of triethylamine. The suspension obtained was heated at a temperature in the region of 80° C. for 3 hours and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 50 cm3 of ethyl acetate in 20 cm3 of water. After stirring the mixture for 15 minutes, the remaining insoluble material was filtered through clarcel and then the filtrate was separated by settling: the organic phase was separated off, then washed with 3 times 3 cm3 of water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The oily residue obtained was purified by. chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 40-63μ; diameter 3 cm; 45 g), elution was carried out with a dichloromethane/methanol (97/3 by volume) mixture. The fractions comprising the expected product were collected. These fractions were concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.345 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetate was obtained in the form of an oil with a pale yellow color. Mass spectrum (El): m/z=506 M+.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.FC1C=CC2C(C3CCNCC3)=NOC=2C=1.[ClH:37]>C(O)(C)C.C(O)C>[ClH:37].[ClH:37].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH3:20])[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Solvent: CCO
Product: CC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65° C. for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO2, 35 g; eluted with methylene chloride, DCM, and CH3OH in DCM). The product thus obtained, weighted 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCl (1M in ether). The salt collected weighed 2.35 g, m.p. >270° C. dec.
Reaction SMILES: [C:1]([C:6]1[C:17]([CH3:18])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]>[O-2].[O-2].[Mn+4]>[C:1]([C:6]1[C:17]([CH3:18])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH:13]=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2nc(CO)n(C)c2cc1C
Agent: [Mn+4]
Agent: [O-2]
Product: CCCC(=O)c1cc2nc(C=O)n(C)c2cc1C
Temperature: 10 °C

Procedure:
25 g of manganese dioxide are activated in 200 ml of alcohol-free chloroform for 2 hours by azeotropic dehydration. The solution is cooled, whilst stirring, to 10° C., 4.92 g of 5-butyryl-1,6-dimethylbenzimidazole-2-methanol are added and the whole is allowed slowly to return to room temperature and is stirred for 18 hours at room temperature. The solution is filtered, the filtrate evaporated to dryness and the residue recrystallised from chloroform/petroleum ether. 5-butyryl-1,6-dimethylbenzimidazole-2-carboxaldehyde having a melting point of 116.5°-118° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:70]1[CH:83]=[CH:82][C:73]([O:74][CH2:75][C:76](=[O:81])[C:77]([CH3:80])([CH3:79])[CH3:78])=[C:72]([CH3:84])[CH:71]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:58]2[CH:57]=[CH:56][C:55]([C:52]([C:70]3[CH:83]=[CH:82][C:73]([O:74][CH2:75][C:76](=[O:81])[C:77]([CH3:80])([CH3:79])[CH3:78])=[C:72]([CH3:84])[CH:71]=3)([CH2:50][CH3:51])[CH2:53][CH3:54])=[CH:60][CH:59]=2)[CH:10]=1
Reactant: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 28.6 mg, 0.124 mmol), palladium acetate (1.8 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.0 mg, 0.017 mmol), potassium phosphate (53 mg, 0.249 mmol) and water (0.2 mL) were added to a solution of 1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example 143-(4); 39.7 mg, 0.083 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (30.4 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:30])([F:29])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][C:25](=O)[CH2:24][C:23](=[O:28])[CH2:22]2)=[CH:17][CH:16]=1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:25]1[CH2:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:30])([F:29])[F:13])=[CH:16][CH:17]=2)[CH2:22][C:23](=[O:28])[CH:24]=1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CC(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COC(=O)c1cccc(NC2=CC(=O)CC(c3ccc(C(F)(F)F)cc3)C2)c1Br
Temperature: 150 °C
Yield: 67.4 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (10.2 g, 44.3 mM) and 5-(4-trifluoromethylphenyl)-1,3-cyclohexanedione (1.77 g, 6.93 mM) was heated at 150° C. under a stream of nitrogen for 20 minutes. The resultant solid was triturated with 4:1 EtOAc/Et2O to afford 2.18 g (74%) of 3-(3-carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl)-cyclohex-2-en-1-one. 1H NMR (DMSO-d6) δ8.9 (s, 1H), 7.75-7.5 (m, 7H), 3.9 (s, 3H), 3.5 (m, 1H), 2.9 (dd, J=14 and 9 Hz, 1H), 2.7 (dd, J14 and 4 Hz, 1H), 2.55 (dd, J=14 and 9 Hz, 1H), 2.35 (dd, J=14 and 4 Hz, 1H). MS (ES) m/e 368, 370.
Reaction SMILES: [C:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)#[N:2]>[Ni].CO>[NH2:2][CH2:1][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CC1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)C1(CN)CC1
Reaction time: 24 h
Yield: 72.9 %

Procedure:
In a 500-mL Parr shaker vessel, Raney nickel (750 mg) was added to MeOH (30 mL). Ethyl 1-cyanocyclopropanecarboxylate (Aldrich; 2.0 g, 14.38 mmol) was added and the resulting mixture was shaken vigorously under an H2 atmosphere (50 psi) for 24 h. The mixture was subsequently filtered through Celite, washing the Celite pad with MeOH (2×20 mL). The combined filtrates were concentrated in vacuo to provide ethyl 1-(aminomethyl)cyclopropanecarboxylate (1.5 g, 10.48 mmol, 73% yield): 1H NMR (400 MHz, CDCl3): δ 4.13 (q, 2H, J=7.2 Hz), 3.67 (s, 1H), 3.44 (s, 1H), 2.74 (br s, 2H), 1.27-1.21 (m, 5H), 0.80-0.74 (m, 2H). m/z (ESI, +ve) 144.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH3:17][NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([CH3:35])[C:25]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=1)=[O:20]>>[CH3:17][NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([CH3:35])[C:25]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)[N:28]=1)=[O:20]
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-4-methyl-thiophene-2-carboxylic acid methylamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 308c. Product isolated as a yellow foam (120 mg, 70%). LCMS (m/e) 501 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.08 (s, 1H), 7.23 (s, 1H), 7.09-7.05 (m, 2H), 6.93 (d, 1H, J=8.0 Hz), 6.81 (s, 1H), 5.98-5.91 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.96 (d, 3H, J=4.8 Hz), 2.90-2.85 (m, 2H), 2.82-2.66 (m, 8H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Yield: 82.7 %

Procedure:
A solution of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.0 g) in 80% aqueous sulfuric acid (30 ml) was cooled to 0° to 5° C., and 60% nitric acid (1.6 g) was gradually added thereto at 0° to 5° C. The resultant mixture was stirred at the same temperature for 30 minutes and poured onto ice water. The precipitated crystals were collected by filtration, washed with water and dried to give 7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.1 g) as pale brown crystals. m.p., 205.9° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](N)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[OH-:18].[K+].Cl>OCCOCCO.C(OCC)C>[CH2:1]([C:3]1[C:8]([C:9]([OH:18])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1c(C(N)=O)cccc1-c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: OCCOCCO
Product: CCc1c(C(=O)O)cccc1-c1ccccc1
Temperature: 0 °C
Yield: 104.5 %

Procedure:
A stirred solution of 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.1 g, 0.0093 mole) and potassium hydroxide (26.3 g, 0.4 mole) in 175 ml of 2-hydroxyethyl ether was heated at 163° for approximately 18 hours. The reaction mixture was cooled and diluted with 150 ml of ice water. The solution was acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was isolated by filtration and dissolved in diethyl ether; the ethereal solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxylic acid (2.2 g) as a solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[NH:9][CH2:10][CH2:11][N:12]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.I[CH3:31]>CN(C=O)C>[CH3:31][N:9]([C:4]1[N:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:10][CH2:11][N:12]([CH2:25][C:26]([F:27])([F:28])[F:29])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:23])([F:22])[F:24])[CH:14]=1
Reactant: N#Cc1ccc(N(CCNc2ncccn2)CC(F)(F)F)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)c1ncccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
NaH (60% in oil, 0.003 g, 0.075 mmol) was added to an ice-cold solution of 4-[[2-(pyrimidin-2-ylamino)ethyl](2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.020 g, 0.051 mmol) in DMF (3 mL), under N2. After stirring for 5 min, iodomethane (0.011 g, 0.078 mmol) was added and stirred for 30 min. The mixture was partitioned between Et2O and water. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes gradient) and the product crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.014 g, 68% yield): MS (ES) m/z 404 (M+1).
Reaction SMILES: N12CCN(CC1)CC2.[NH2:9][C:10]1[N:19]=[C:18]([NH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:16]=2)[N:11]=1.[OH-:30].[NH4+]>C(O)(=O)C>[NH2:9][C:10]1[N:19]=[C:18]([NH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[O:30])[CH:16]=2)[N:11]=1
Reactant: [OH-]
Reactant: Nc1nc(N)c2cc(Sc3ccc(Cl)c(Cl)c3)ccc2n1
Agent: C1CN2CCN1CC2
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(S(=O)c3ccc(Cl)c(Cl)c3)ccc2n1

Procedure:
A suspension of 5.0 grams (0.011 mole) of the bromine complex of 1,4-diazabicyclo(2,2,2)octane in 200 mL of aqueous 70% acetic acid was stirred, and 3.4 grams (0.01 mole) of 2,4-diamino-6-(3,4-dichlorophenylthio)quinazoline was added portionwise during about a 1 hour period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. After this time, the reaction mixture was neutralized with concentrated ammonium hydroxide. The resultant solid was collected by filtration and triturated with methanol. The solid was collected by filtration and dried, yielding 2,4-diamino-6-(3,4-dichlorophenylsulfinyl)quinazoline, mp 200° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12](=[S:37])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:28]4[CH:27]=[CH:26][N:25]=[C:24]([NH:29]C(=O)OC(C)(C)C)[C:23]=4[CH:22]=[CH:21]3)=[CH:16][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[NH2:29][C:24]1[C:23]2[CH:22]=[CH:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:37])=[CH:19][CH:18]=3)[C:28]=2[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2c1ccn2-c1ccc(NC(=S)NC(=O)Cc2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccc2c1ccn2-c1ccc(NC(=S)NC(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 1-(4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenyl)-1H-pyrrolo[3,2-c]pyridin4-ylcarbamate (10 mg, 0.19 mmol) was treated with 4 N HCl in dioxane (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the remaining solid was triturated twice with EtOAc (˜0.5 mL) to afford the title compound as the hydrochloride salt (6.5 mg, 74%). 1H NMR (DMSO-d6) δ 12.48 (s, 1H), 11.80 (s, 1H), 8.42 (br s, 2H), 7.88 (d, 2H, J=8.5 Hz), 7.78 (d, 1H, J=3.1 Hz), 7.64-7.55 (m, 3H), 7.38 (dd, 2H, J=7.6, 6.2 Hz), 7.27 (d, 1H, J=3.1 Hz), 7.18 (t, 2H, J=9.7 Hz), 6.97 (d, 1H, J=7.0 Hz), 3.83 (s, 2H); LCMS (ESI+) m/z 420 (M+H)+; HPLC tR=3.42 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([Mg]Br)=[CH:21][CH3:22]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:14]([OH:15])[CH:20]=[CH:21][CH3:22])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC=C[Mg]Br
Solvent: C1CCOC1
Product: CC=CC(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 56 %

Procedure:
Analogously to the procedure of example II, starting from 3.00 g (11.66 mmol) of 5-benzyloxy-2-nitrobenzaldehyde in 60 ml of THF and 37.8 ml (18.66 mmol) of a 0.5 M 1-propenylmagnesium bromide solution in THF at −78° C., 1.95 g (56%) of 1-[5-(benzyloxy)-2-nitrophenyl]-2-buten-1-ol are obtained as an E/Z mixture.