Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][C@H:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:15][C:30]3=[O:32])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1O[C@@H](c2ccccc2)CN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of (S)-2-((1-adamantylmethyl)amino)-1-phenylethanol (35 mg, 0.12 mmol), Et3N (24.8 mg, 0.25 mmol) in CH2Cl2 (2 mL) at 0° C. was added triphosgene (14.6 mg, 0.05 mmol) and the mixture was stirred for 30 min. The mixture was concentrated under vacuum to give the crude product, which was purified by preparative TLC to give (S)-3-((1-adamantyl)methyl)-5-phenyloxazolidin-2-one (10 mg, 26%). 1H NMR (MeOD, 400 MHZ): δ=1.51-1.95 (m, 15H), 2.89 (q, 2H), 3.55 (q, 1H), 4.10 (t, 1H), 5.57 (q, 1H), 7.34˜7.45 (m, 5H); MS m/z=312.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(C(F)(F)F)C=CC=1.[Mg].[CH:25]([N:38]1[CH2:41][CH2:40][CH:39]1[C:42]#[N:43])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH:25]([N:38]1[CH2:41][CH2:40][CH:39]1[C:42](=[NH:43])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#CC1CCN1C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Agent: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: N=C(c1cccc(C(F)(F)F)c1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Suspend m-trifluoromethylphenylmagnesium bromide in ether by adding a solution of 18 g of m-bromobenzotrifluoride in 30 ml of ether to a stirred suspension of 1.94 g of magnesium turnings in 20 ml of dry ether. Upon completion of addition, allow the reaction mixture to cool to room temperature and add 7.95 g of 1-benzhydryl-2-cyanoazetidine. Stir the mixture for 18 hours at room temperature, cool to 0° C. or lower, and quench by the dropwise addition of 50 ml of water. Add 15 ml of ether and 25 ml of methylene chloride and filter the mixture through a pad of diatomaceous earth, such as commercially available Celite. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo to obtain the title compound as an oil. By suitable substitution, analogous halo compounds can be prepared.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2B(O)O)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([NH:21][C:22](=[O:39])[CH2:23][O:24][CH2:25][C:26]([NH:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:20]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:29]([NH:28][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([NH:21][C:19]2[CH:20]=[C:15]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)[CH:16]=[CH:17][C:18]=2[CH3:40])=[O:39])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: OB(O)c1cccc2cccnc12
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Product: Cc1ccc(-c2cccc3cccnc23)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 19-(ii), 8-quinoline boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 38-(i) to give 5-chloro-2-([(2-([2-methyl-5-(quinolin-8-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 53%).
Reaction SMILES: [CH2:1]([NH:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCCCC>[CH3:20][N:21]([CH3:25])[C:22]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[OH:12])=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: CCCCCCCCCCNO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCN(O)C(=O)N(C)C
Temperature: 5 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred slurry of N-decylhydroxylamine (1.71 g, 9.91 mmol) in the THF (20 ml) at room temperature under nitrogen was added triethylamine (1.51 ml, 1.1 equiv.). The reaction mixture was cooled to 5° C. and dimethyl carbamyl chloride (0.92 ml, 1.05 equiv.) was added dropwise over five minutes. After stirring for two hours, the mixture was poured into 1% aqueous citric acid, and worked up as in Example 1 above. Trituration with pentane gave the named compound as a white solid (2.15 g, 89% Yield), mp 44°-45° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:18][CH2:17][CH2:16]2)[C:8]1=O.O>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:18][CH2:17][CH2:16]2)[CH2:8]1
Reactant: O=C1Nc2ccccc2C12CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NCC21CCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 0.60 mL (0.60 mmol) of a 1M solution of lithium aluminium hydride in THF was added dropwise to 100 mg (0.58 mmol) spiro[cyclobutan-1,3′-indolin]-2′-one in 20 mL THF. Then the reaction mixture was stirred for 1 h at 65° C. After cooling 1 mL water was added and the mixture was stirred for 10 min. The organic phase was dried on sodium sulphate and evaporated down. The product was reacted without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][Cl:18])=[O:15].[OH2:19]>C(OCC)C.C(OCC)(=O)C>[C:14](=[O:19])([O:15][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[O:16][CH2:17][Cl:18]
Reactant: COCCCO
Reactant: O
Reactant: O=C(Cl)OCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: COCCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-(methoxy)propanol (6.0 g), pyridine (5.3 g) and diethyl ether (50 ml), a solution of chloromethyl chloroformate (8.6 g) in diethyl ether (10 ml) was added dropwise under ice cooling over the period of 15 minutes. After stirring at room temperature for 16 hours, water (100 ml) and ethyl acetate (100 ml) were added, and the organic layer was separated. The organic layer was washed with water (100 ml) and a saturated sodium chloride aqueous solution (50 ml), and after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 70 g, eluent: ethyl acetate-hexane=1:2) to obtain chloromethyl [3-(methoxy)propyl] carbonate (11.0 g) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:3]=12.[Cl:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[ClH:20].[CH2:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:3]2[C:4](=[N:5][C:6]3[C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:15][CH2:16]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3c([N+](=O)[O-])cccc13)CCNCC2
Product: CCOC(=O)N1CCc2nc3c([N+](=O)[O-])cccc3c(C)c2CC1
Product: Cl
Yield: 70 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-7-nitro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-7-nitro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].CC1C=C(C=C(C)N=1)CCl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=[O:23]>N1C=CC=CC=1.S(Cl)(Cl)=O>[NH2:5][C:3](=[O:4])[CH:2]([NH:1][C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:28])[N:27]=[C:19]([CH3:18])[CH:20]=1)[C:6]#[N:7]
Reactant: N#CC(N)C(N)=O
Reactant: Cc1cc(C(=O)O)cc(C)n1
Agent: Cc1cc(CCl)cc(C)n1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)NC(C#N)C(N)=O)cc(C)n1
Yield: 43.8 %

Procedure:
2-amino 2-cyano acetamide (1.4 g, 0.01473 mol, 1 eq) in pyridine (15 ml) is stirred for 1 h at room temperature, to this 2,6-dimethyl isonicotinyl chloride (2.5 g, 0.1473 mol, 1 eq) [prepared by stirring a mixture of 2,6-dimethyl isonicotinic acid (2.5 g, 0.0465 mol, 1 eq) in thionyl chloride (15 ml) at 85° C. for 2 hr, thionyl chloride was removed in vacuum under nitrogen] is added at 0° C. and the reaction mixture is stirred at room temperature for 14 h, after the completion of the reaction pyridine is removed under vacuum and the crude product is purified by column chromatography to afford (1.5 g) of the titled compound;
Reaction SMILES: [C:1]1([CH:7]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][C:9](=O)[C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[C:1]1([CH:7]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC2=C1C(c1ccccc1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccccc1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 9-phenyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), sodium borohydride (6.5 g), ethanol (150 mL) and pyridine (50 mL) was heated at 70° C. overnight and cooled to room temperature. The solvent was removed, the residue partitioned between water and ethyl acetate, the organic layer was dried and the solvent removed. Chromatography (methylene chloride/methanol; 98/2) provided the title compound (3.0g) as a white solid. Recrystallization from ethanol/hexane returned analytically pure title compound, mp 252°-254° C., NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.03-2.13 (m,4, CH2), 2.38-2.44 (m,2, CH2), 4.14 (s,1, CH), 7.04-7.21 (m,5, Ar) 8.34 (s,1, NH); (CI, CH4) MS: m/z=280(M+1). Analysis for C19H21NO.0.2H2O: Calculated: C, 80.64; H, 7.62; N, 4.95; Found: C, 80.84; H, 7.62; N, 4.80.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29])[CH2:2][CH2:3][CH3:4].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCCCCC>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[C:28]([OH:32])=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: O=P([O-])(O)O
Reactant: CCCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OC)c3)c2cc1OC
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCOc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OC)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
To a stirred solution of afforded 6-butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (131 mg, 0.33 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (184 mg, 1.33 mmol), 2-methyl-2-butene (0.226 mL, 2.00 mmol) and sodium chlorite (181 mg, 2.00 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichlormethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate and hexane to afford 6-butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (35 mg, 62% yield) as a light yellow solid. HR-MS m/e calcd for C26H21N1O6 (M−H+) 444.1442, found 444.1442; 1H NMR (300 MHz) compatible.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29](Br)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[N:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cnc(Br)cn1
Product: Nc1cnc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 2-amino-5-bromo-pyrazine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (53 mg, 25%). MS (ISP) 431.2 [(M+H)+]; mp 233° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)ccc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-2-fluorobenzenesulfonamide (231 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 35%). MS (ISP) 587.2 [(M+H)+]; mp 247-249° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][N:14]([CH3:29])[CH2:15][CH2:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26].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>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH2:16][CH2:15][N:14]([CH3:29])[CH3:13])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CN(C)CCOc1ncc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOc1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol), 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (107 mg, 0.429 mmol) and HATU (245 mg, 0.644 mmol) in DCM (15 mL) was added DIEA (0.225 mL, 1.287 mmol). The resulting mixture was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to yield a brown oil of 2-(4-bromo-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (130 mg, 0.273 mmol, 63.7% yield): 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.38-7.26 (m, 4H), 4.62 (t, J=5.4 Hz, 2H), 3.75 (s, 2H), 3.08 (t, J=5.2 Hz, 2H), 2.56 (s, 6H); ES-LCMS m/z 464.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[N:6][CH:7]=1.[CH2:12](N(CC)CC)[CH3:13].CS(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][O:11][CH2:12][CH3:13])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: OCC=Cc1ccc(Br)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOCC=Cc1ccc(Br)cn1
Reaction time: 0.42 h
Yield: 65 %

Procedure:
5-Bromo-2-(3-hydroxy-1-propenyl)pyridine (3.718 g) was dissolved in tetrahydrofuran (60 ml), followed by the sequential addition of triethylamine (7.1 ml) and methanesulfonyl chloride (1.6 ml) under ice-cooling, and the resulting mixture was stirred as it was, for 25 min. After the resulting insoluble matters were filtered off, the mixture was evaporated. The resulting residue was dissolved in ethanol (60 ml), followed by the addition of sodium ethoxide (1.388 g)/ethanol (25 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was evaporated, and the resulting residue was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (2.607 mg, yield; 65%).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccc1
Yield: 88 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride. Yield: 88% of theory, C34H32N6O4 (588.7) Rf value: 0.37 (silica gel; dichloromethane/ethanol=19:1) 1H-NMR spectrum (D6 -DMSO): 2.61 (t,2H), 3.54 (s,3H), 3.76 (s,3H), 4.10 (t,2H), 4.61 (d,2H), 6.83 (d,2H), 7.05 to 7.55 (m,12H),8.03 (d,2H), 8.25 (dd,2H), 8.98 (s,1H), 10.48 (s,1H)
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([OH:38])=O)[CH:27]=[CH:28][CH:29]=1.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[NH:40]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:51][C:48]([F:49])([F:50])[C:47]([NH:46][CH2:45][C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:36]([C:31]1[N:32]=[C:33]([CH3:35])[S:34][C:30]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=1)=[O:38])=[O:52]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
TBTU (3.22 mmol, 1.05 eq) is added to a solution of 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.07 mmol, 1.0 eq), N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (3.07 mmol, 1.0 eq) and DIPEA (9.20 mmol, 3.0 eq) in DCM (15 mL). After 2 h the mixture is washed twice with water, once with sat. aqueous NaHCO3 solution, once with hydrochloric acid (0.2 M) and three times with water. The organic layer is dried over Na2SO4, the solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: DCM to DCM/MeOH 19/1) and preparative TLC (DCM/MeOH 19/1) to give the desired product as an orange foam. LC-MS (acidic): tR=0.97 min; [M+H]+=428.1.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[CH3:16][C:17]1([CH3:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]1.O>ClCCl>[CH3:16][C:17]1([CH3:29])[CH2:18][CH2:19][C:20]([CH3:28])([CH3:27])[C:21]2[CH:22]=[C:23]([C:13](=[O:14])[CH2:12][C:9]3[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][CH:8]=3)[CH:24]=[CH:25][C:26]1=2
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Cc3ccc(Br)cc3)ccc21
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Aluminium trichloride (4.33 g, 32.5 mmol) and 4-bromophenylacetyl chloride (5.55 g, 23.2 mmol) are added successively at −30° C. to a solution of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.36 g, 23.2 mmol) in 300 ml of dichloromethane. The temperature is allowed to rise to 0° C. in 30 minutes, the reaction mixture is poured over 400 ml of a volume to volume mixture of ice and water and this is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The raw product is purified by crystallisation in hexane to obtain 5.69 g of a white solid, 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-oxo-2-ethyl]bromobenzene (yield=63%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1cccs1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1cccs1
Yield: 42.2 %

Procedure:
Following a similar treatment to that in Example 33 and using 0.38 g of 2-thiophenecarboxylic acid and 0.50 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Brc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1csc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 50.8 %

Procedure:
A mixture of 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (170 mg, 0.64 mmol, 1.0 equiv.), thiophen-2-ylboronic acid (107 mg, 0.83 mmol, 1.3 equiv.), Pd(PPh3)4 (148 mg, 0.128 mmol, 0.2 equiv.), Na2CO3 (238 mg, 2 mmol, 3.5 equiv.), 1,4-dioxane (5 ml) and water (1 ml) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool down to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1 as eluent) to afford title compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(thiophen-2-yl)pyrimidin-4-amine (Compound 27)(92.2 mg, 50.9%) as solid. LC-MS (m/z)=284.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.71 (m, 2H), 0.95 (m, 2H), 1.94 (m, 1H), 6.35 (s, 1H), 6.87 (s, 1H), 7.17 (m, 1H), 7.70 (m, 1H), 7.83 (d, J=2.8 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 9.91 (s, 1H), 12.08 (s, 1H).