Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](=O)[CH2:14]Br)[CH3:10]>C1(C)C=CC=CC=1.O>[CH2:9]([O:11][C:12]([C:13]1[N:8]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]2[CH:14]=1)=[O:17])[CH3:10]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Br)ccn1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn2ccc(Br)cc2n1
Temperature: 115 °C
Yield: 104.5 %

Procedure:
To a stirred solution of 4-Bromo-pyridin-2-ylamine (4 g, 23.12 mmol) in toluene (40 mL) is added 3-Bromo-2-oxo-propionic acid ethyl ester (4.5 g, 23.12 mmol). The reaction mixture is heated at 115° C. for 16 hours. Reaction mixture is cooled to 0° C. then diluted with water and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo to afford the title compound (6.5 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.31 (t, J=7.2 Hz, 3H), 4.26-4.33 (q, J=7.2 Hz, 2H), 7.18-7.20 (dd, J1=1.92 Hz, J2=7.16 Hz, 1H), 7.98 (s, 1H), 8.53 (d, J=7.32 Hz, 1H), 8.57 (s, 1H). LC-MS (m/z): [M+H]=271.0.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][F:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][F:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(N)C1
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Fluoroethyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 0.012 g (35%) of 2-fluoroethyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.60-7.65 (m, 2H), 7.49-7.51 (m, 1H), 7.29-7.39 (m, 4H), 6.87 (s, 1H), 4.66-4.69 (m, 1H), 4.54-4.58 (m, 1H), 4.39-4.43 (m, 1H), 4.32-4.36 (m, 1H), 3.73 (s, 2H), 3.58-3.68 (m, 4H), 3.43-3.52 (m, 2H), 1.78-1.87 (m, 2H), 1.65-1.75 (m, 2H), 0.90-0.96 (m, 3H); ink (APCI-pos) M+1=482.2.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[I:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([NH2:20])=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[I:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]#[N:20]
Reactant: Cc1ccc(C(N)=O)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc(C#N)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
2,2,2-trifluoroacetic anhydride (8.00 mL, 57.5 mmol) was added dropwise to a stirred solution of 3-iodo-4-methylbenzamide (preparation 48a, 6.00 g, 23.0 mmol) and triethylamine (8.10 mL, 57.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. Further dichloromethane and saturated aqueous potassium carbonate solution were added and the organic layer was washed with 2M aqueous hydrochloric acid, 2M aqueous sodium hydroxide solution, brine, dried (MgSO4) and evaporated to give the title compound (4.50 g, 80%) as a pale orange solid.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.C1(C(C)C(O)=O)C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH:13]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: CC(C(=O)O)c1ccccc1
Product: CC(C)c1ccc(C(=O)C(C)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-phenylpropionic acid, mp 142°-144° C.
Reaction SMILES: CC1C=CC(S(C(C2C=CC=C(I)C=2)[N+]#[C-])(=O)=O)=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:39][CH:40]=O)[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1.IC1C=C(C(NC=O)S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1>>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH:28]([C:25]2[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][CH:26]=2)[N+:39]#[C-:40])(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(Br)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Agent: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Product: [C-]#[N+]C(c1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 53 but using {(4-bromophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 65) in place of {(3-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 52). Brown solid (3.1 g, 29%);
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:5][CH:4]=1.Cl.[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:25]2([OH:31])[CH2:26][CH2:27][N:28]([C:11]([C:10]3[C:9]([C:6]4[CH:7]=[CH:8][N:3]=[CH:4][N:5]=4)=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:13])[CH2:29][CH2:30]2)=[CH:32][CH:33]=1
Reactant: O=C(O)c1cccnc1-c1ccncn1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1-c1ccncn1)N1CCC(O)(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.25 g), 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (0.22 g), HATU (0.52 g) and triethylamine (0.76 mL) in DMF (3 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.050 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.7) (0.19 g, 0.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.15 g, 0.6 mmol) according to the general procedure III. Obtained as off-white solid (0.16 g), which was subsequently deprotected.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2ccccc2)c(N)c1
Yield: 96 %

Procedure:
A solution of 2.4 g of 3-nitro-4-phenyltoluene in 25 mL of methanol was hydrogenated at room temperature and 40 psi over 0.30 g of 5% Pd/C catalyst. The solution was filtered and the filtrate concentrated to give 1.98 g of product. EI-MS: calculated for C13H13N: 183; found 183.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH:9]2O)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2ccc(Br)cc2C(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C=Cc2cc(Br)ccc2C1
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-1-naphthol (7.0 g) and p-toluene sulphonic acid (0.5 g) in benzene (100 ml) was heated under reflux, using a Dean-Stark water separator, for 1.5 hours. After cooling, solvent was removed in vacuo, and the residue partitioned between ether and water. The combined ether extracts were washed with sodium bicarbonate solution, water, brine, then dried over sodium sulphate. Removal of drying agent and solvent gave the title compound as an oil (6.2 g) having:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([CH3:13])[N:9]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21](OC)=[O:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]>C1COCC1.[Cl-].[Na+].O>[CH3:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([CH3:13])[N:9]1[CH2:14][C:15]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2[C@H](C)CC[C@H]2C)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO)cc2CN2[C@H](C)CC[C@H]2C)c1
Temperature: 25 °C
Reaction time: 0.55 h
Yield: 98.2 %

Procedure:
LAH (1.0 M solution in THF) (0.086 mL, 0.086 mmol) was added slowly to a solution of 66.71A (0.032 g, 0.086 mmol) in THF (1.5 mL) and the mixture was stirred at room temperature for 33 minutes. The mixture was poured into brine (2 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. After removing solvent, 66.71B (29 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:29]=1)=O.[CH3:30][NH:31][CH3:32].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:30][N:31]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:29]=1)[CH3:32]
Reactant: CNC
Reactant: N#Cc1cncc(-c2cc3cc(C=O)ccc3s2)c1Nc1cccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2sc(-c3cncc(C#N)c3Nc3cccc4[nH]ccc34)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To 5-(5-formyl-1-benzothien-2-yl)-4-(1H-indol-4-ylamino)nicotinonitrile 223 (166 mg, 0.38 mmol) in THF (7 mL) was added dimethylamine in THF (2.0 M, 0.58 mL, 1.15 mmol) followed by acetic acid (126 mg, 2.09 mmol). The resulting mixture was stirred at r.t. for 1 h and additional dimethylamine (1.2 mL, 2.30 mmol) was added. After stirring at r.t. for an additional hour, Na(OAc)3BH (242 mg, 1.15 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and was partitioned between diluted HCl and EtOAc. The combined aqueous extracts were basified with aqueous NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, concentrated and purified by flash column chromatography to give 115 mg (65%) of 5-{5-[(dimethylamino)methyl]-1-benzothien-2-yl}-4-(1H-indol-4-ylamino)nicotinonitrile 224 as a pale yellow solid. MS: 424.2 (M+H); HPLC retention time: 2.1 min.(a).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][S:25][C:26]4[N:30]=[CH:29][N:28](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:27]=4)[CH:17]=3)=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][S:25][C:26]4[N:30]=[CH:29][NH:28][N:27]=4)[CH:17]=3)=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Cc1csc2nc(C(=O)NCc3ccnc(OCCSc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc2nc(C(=O)NCc3ccnc(OCCSc4nc[nH]n4)c3)[nH]c(=O)c12
Yield: 21 %

Procedure:
A solution of 5-methyl-4-oxo-N-({2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridin-4-yl}methyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide (395.0 mg, 0.576 mmol), triethylsilane (0.097 mL, 0.605 mmol) and trifluoroacetic acid (3.0 mL) in dichloromethane (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-IPE to give the title compound as a white powder (53.6 mg, 21%).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH:32]1([C:35]2[C:36]([NH:52][C@@H:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:55][C@@H:54]3[OH:62])=[N:37][C:38]([CH:49]3[CH2:51][CH2:50]3)=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[N:40]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([NH:52][C@@H:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:55][C@@H:54]3[O:62][CH2:2][CH3:3])=[N:37][C:38]([CH:49]3[CH2:50][CH2:51]3)=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[N:40]=2)[CH2:33][CH2:34]1
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.80-1.07, 1.17-1.20, 1.67, 1.79, 3.14-3.20, 3.46-3.50, 3.70-3.72, 4.35, 5.72, 5.97, 7.24-7.50; MS (ESI+) for C27H27Cl2N3O m/z 480 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:20]([CH2:22][C:23](Cl)=[O:24])#[N:21]>O1CCCC1>[C:20]([CH2:22][C:23]([NH:4][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1])=[O:24])#[N:21]
Reactant: N#CCC(=O)Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c([N+](=O)[O-])cc1NC(=O)CC#N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 76.6 g (0.455 mol) of 2,4-dimethyl-5-nitroaniline and 64 ml (0.46 mol) triethylamine in 500 ml abs. tetrahydrofurane is added dropwise within 1 h 47.2 g (0.455 mol) cyanoacetyl chloride in 100 ml tetrahydrofurane. After stirring for 2 h at 25° C. and 3 h at 80° C. and cooling to 25° C. the reaction mixture is filtered and poured into water. The precipitate is separated, washed with water and toluene/petrolether and dried. Yield: 84 g (78%) N-cyanoacetyl-2,4-dimethyl-5-nitroaniline, mp. 229°-230° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:23]=2[CH3:22])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1cc(OC)cc(Oc2ccc(C=O)cc2)c1
Product: C=CCOc1cc(OC)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 90B and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the title compound. MS (ESI−) m/z 419 (M−H)−.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: C1CSCCN1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCSCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 60 mg; 0.20 mmol) and thiomorpholine (0.20 mL; 2.0 mmol) to 250° C. under microwave irradiation according to the procedure described in Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-thiomorpholin-4-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (15 mg, 21%) as light brown powder. ES-HRMS m/e calcd for C19H29N4OS4 (M+H+) 361.2057, found 361.2053.
Reaction SMILES: C(C=C[C@@:8]1([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)(OCC)=O.[OH-:24].[Na+]>>[C:10](/[CH:9]=[CH:8]/[C:22]1[C:20]([NH2:21])=[N:19][C:17](=[O:18])[N:16]([CH:23]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)([OH:11])=[O:24]
Reactant: CCOC(=O)C=C[C@]1(n2ccc(N)nc2=O)C[C@H](O)[C@@H](CO)O1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbethoxyvinyldeoxycytidine (325 mg, 1mmol) is suspended in 0.5M NaOH solution (40 ml) and stirred at room temperature for 2 hrs. The clear solution is neutralised by addition of Dowex-50H+ -form to pH 7 and filtered. This solution is immediately used for the preparation of E-5-(2-bromovinyl)-2'-deoxycytidine.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Br>>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccncc2)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccc(-c2ccncc2)cc1

Procedure:
In the process according to claim 1, the step which comprises reacting 4-(4-dimethylaminophenyl)pyridine with pyridine hydrochloride or hydrobromide at about 130°-260°C. to yield 4-(4-aminophenyl)pyridine.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19])[OH:17]>CC(C)=O>[O:17]1[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2ccccc2O1

Procedure:
26 g (100 mmol) of ethyl 2,3-dibromopropionate and 36.4 g (264 mmol) of anhydrous potassium carbonate are added to 40 g (181 mmol) of catechol dissolved in 200 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the reaction mixture is then heated to boiling. After 18 hours at reflux under argon, the mixture is cooled and then filtered over Celite. After concentration of the filtrate in vacuo, the residue is hydrolysed and then the aqueous phase is extracted with ether. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The title ester is obtained pure by distillation under reduced pressure (15 mm Hg; b.p.=155° C.).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Sn:22]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])OC)[CH2:19][CH2:20][CH3:21]>ClCCCl>[CH2:29]([Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:25][CH2:26][CH2:27][CH3:28])[O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)OC
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)OC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 41.9 %

Procedure:
In a 50 ml dry three-neck-flask, 2.0 g (8.8 mmol) 4-benzoylbenzoic acid in 30 ml 1,2-dichlorethane are suspended under argon flow and heated to reflux. 2.8 g (8.8 mmol) tri-n-butylmethoxy tin are added slowly in the course of 0.5 h. The conversion is complete according to the 1H-NMR-spectrum. The slightly turbid hot solution is filtered, cooled and concentrated. 3.6 g of the crude product are obtained as yellowish oil. 2.4 g thereof are heated in a bulb-to-bulb distillation apparatus (0.03 mbar) and distilled at 190° C. 1.9 g of the title product is obtained as colorless oil. The structure is confirmed by 1H-NMR and 13C-NMR-spectra.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CN1CCC(c2cccnc2F)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1=O
Temperature: 120 °C
Yield: 37.1 %

Procedure:
Into a sealed tube were added 4-(2-fluoropyridin-3-yl)-1-methylpiperidin-2-one (0.06 g, 0.288 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.223 g, 0.922 mmol), cesium carbonate (0.310 g, 0.951 mmol), and 1-methyl-2-pyrrolidinone (1 mL). After degassing for 5 min, the reaction was heated at 120° C. for 14 h. The cooled mixture was diluted with EtOAc and washed with water; the aqueous layer was back-washed with EtOAc (1×). The combined organic extracts were washed with aqueous 1N NaOH solution, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 100% EtOAc/Hexanes) afforded 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-1-methylpiperidin-2-one (0.046 g, 37.1% yield) as a tan amorphous solid. MS (ESI, pos. ion) m/z: 431.9 (M+1). IC50 (uM) +++++.