Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](O)(=O)[CH3:28].C(=O)C>C1COCC1>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Agent: CC=O
Solvent: C1CCOC1
Product: CCN1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was dissolved in 0.5 ml THF. Acetic acid (0.01 ml; 0.23 mmol), acetaldehyde (0.03 ml; 0.46 mmol) and STAB (0.03 g; 0.15 mmol) were added and stirred at ambient temperature for 3 hours. The crude material was purified by using reversed phase chromatography under basic conditions and afterwards by TLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Cc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-fluorobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.18 (1H, d, J=7.7 Hz), 8.65 (1H, d, J=2.6 Hz), 7.96 (1H, d, J=2.6 Hz), 7.93 (2H, d, J=8.3 Hz), 7.50 (2H, d, J=8.4 Hz), 7.27–7.20 (1H, m), 7.02–6.89 (3H, m), 5.20–5.10 (1H, m), 4.20 (1H, d, J=14.1 Hz), 4.13 (1H, d, J=14.1 Hz), 3.85 (3H, s), 1.42 (3H, d, J=7.2 Hz); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]=2[N:11]=1.[O:22]=[C:23]1[NH:28][CH2:27][CH:26]2[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:25]2[O:24]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[C:8](=[O:21])[CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][CH:26]5[CH2:29][CH2:30][NH:31][CH2:32][CH:25]5[O:24][C:23]4=[O:22])=[N:11][C:10]2=3)=[CH:14][CH:15]=1
Reactant: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC(=O)OC2C1
Product: COc1ccc(CN2C(=O)COc3ccc(N4CC5CCNCC5OC4=O)nc32)cc1
Yield: 95 %

Procedure:
Starting from 6-bromo-4-(4-methoxybenzyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (prepared as described in WO 2010/041194, 0.35 g, 1 mmol) and rac-(4aR*,8aR*)-tert-butyl 2-oxohexahydro-2H-pyrido[4,3-e][1,3]oxazine-7(3H)-carboxylate (Preparation A, 0.308 g, 1.2 mmol, 1.2 eq.), the title compound was obtained as an orange foam (0.255 g) using the procedures described in Preparation D, steps D.i and D.ii (Buchwald coupling: 95% yield, Boc deprotection: 63% yield).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1.[C:16]([Cu])#[N:17]>CN1CCCC1=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([C:16]#[N:17])[C:3]2=[O:15])=[CH:9][CH:10]=1
Reactant: N#C[Cu]
Reactant: O=c1c(Cl)nccn1-c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: N#Cc1nccn(-c2ccc(F)cc2)c1=O
Temperature: 150 °C
Yield: 23.1 %

Procedure:
A mixture of 3-chloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (3.52 g, 15.7 mmol), CuCN (2.81 g, 31.3 mmol) and N-methylpyrrolidone (30 mL) was heated for 5.5 hours at 150° C. while being stirred. The residue was triturated with hot CHCl3 and filtered over charcoal. The filtrate was evaporated and concentrated under reduced pressure. The residue was triturated with CH2Cl2 and the solution was concentrated. The crude was purified by silica gel flash column chromatography (3:1=CH2Cl2:Hexane then CH2Cl2) to afford 0.78 g (23%) of the desired product. LRMS (ESI pos) m/e 215.9 (M+1).
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CC(C[AlH]CC(C)C)C>C(OCC)C>[CH:7]1([CH2:6]/[CH:5]=[CH:4]/[CH2:3][OH:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)/C=C/CC1CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: OC/C=C/CC1CCCCC1
Temperature: -78 °C
Reaction time: 14 h

Procedure:
To a solution of 12.00 g (65.93 mmol) of <(E)-methyl-4-cyclohexyl-2-butenoate dissolved in 400 mL of diethyl ether cooled to -78° C. was added 215 mL (215 mmol) of DIBAL-H (1.0M in THF). After 0.5 hr the reaction was warmed to 0° C. for 0.5 hr and quenched with 300 mL of aqueous saturated solution of NaK tartrate, this stirred for 14 hr. The aqueous layer was extracted with ether (2×100 mL) and the combined organic layers were washed with water (1×100 mL), brine (1×100 mL), dried over MgSO4 and concentrated to provide (E)-4-cyclohexyl-2-buten-1-ol as colorless oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Yield: 101.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (340 mg, 0.561 mmol) prepared in Example 4b, triethylsilane (0.4 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield the title compound (259 mg, 43%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:44][CH2:43]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 68.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (504 mg, 1.26 mmol, 69%) was obtained.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC(CSCCO)=CC=2)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:16][CH:17]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1ccc(CSCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 68 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (1.65 g, 5.21 mmol, 1 eq.) was treated with phenol (0.69 g, 7.29 mmol, 1.4 eq.), triphenylphosphine (1.91 g, 7.29 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (1.47 g, 1.44 mL, 7.29 mmol, 1.4 eq.). When complete, the reaction was worked up and the product purified by silica gel flash chromatography using 7.5% EtOAc in hexane as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (1.40 g, 68% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]=1[CH3:26])=[O:5])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[C:7]=1[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc([N+](=O)[O-])cc2)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(N)cc2)c1C

Procedure:
2-Methyl-1-(4-nitro-phenyl)-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester of Example 33 (2 mmol, 0.8 g) was dissolved 50% solution of ethyl acetate in ethanol, and treated with Pd/C (0.088 g). The mixture was hydrogenated with H2 (g) at 45 psi. Upon completion of the reaction, the mixture was filtered through Celite and the solvents removed under vacuum. This material was purified over silica gel to yield the named product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1>>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: CCCc1cnc(-c2ccc(Br)cc2)nc1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: CCCc1cnc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)nc1

Procedure:
Analogously to Example 9, by reacting 14.0 g of 2-(4-bromophenyl)-5-propylpyrimidine and 12.1 g of trifluoromethoxy-4-bromobenzene, the corresponding 2-(4'-trifluoromethoxybiphenyl-4-yl)-5-propylpyrimidine having C 125° SG 1110 SA 218° I is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(Cl)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(Cl)c1
Yield: 95.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3-chloro-5-methylpyridin-2-yl)piperazin-1-yl]methanone (626 mg) described in Preparation Example 110 and (R)-4-methyloxazolidin-2-one (227 mg) described in Preparation Example 25, the title compound (627 mg) was obtained.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5]1=[O:20].[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:28]=1[S:29]([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[CH:17]1([CH2:16][NH:15][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([OH:14])=[C:4]([C:3]3[NH:23][C:24]4[S:25][CH:26]=[C:27]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:28]=4[S:29](=[O:31])(=[O:30])[N:32]=3)[C:5]2=[O:20])[CH2:18][CH2:19]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: C1COCCO1
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Yield: 52.3 %

Procedure:
A solution of 3-[bis(methylthio)methylene]-1-[(cyclopropylmethyl)amino] quinoline-2,4(1H,3H)-dione (500.3, 1.5 mmol) and the product of 2-amino-4-[(methoxymethoxy)methyl]thiophene-3-sulfonamide (377.62 mg, 1.5 mmol) in dioxane (15 mL) was stirred at reflux for 1.5 hours and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0% to 10% ethyl acetate/dichloromethane to give 1-[(cyclopropylmethyl)amino]-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}quinolin-2(1H)-one (384.7 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=6.99 Hz, 2 H) 4.64 (s, 2 H) 4.71 (s, 2 H) 6.36 (br s, 1 H) 7.42 (m, 2 H) 7.86 (m, 1 H) 8.07 (d, J=8.46 Hz, 1 H) 8.16 (m, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+]>CO>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1C2CCCC1CN(Cc1ccccc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CC3CCCC(C2)C3N2CCNCC2)cc1

Procedure:
A mixture of 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (0.72 g, 3.14 mmol), methanol (25 ml), piperazine(2.71 g, 31.4 mmol), several 3A molecular sieves, and NaBH3CN (0.39 g, 6.28 mmol) was refluxed for 60 hr, cooled, and concentrated. The residue was taken up in 1N HCl (50 ml), washed with ethyl acetate, the pH adjusted to 12 with 1N NaOH aqueous solution, and extracted with dichloromethane. The extract was dried over Na2SO4 and concentrated to afford 0.72 g (72% crude) of an oil, which was used directly in the following step.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:32]=2[N:23]=[CH:24][CH:25]=[CH:26]3)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (4.50 mg, 1.44 mmol) in acetonitrile (30 ml) were added 8-quinolinecarboxylic acid (249 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (162 mg, 24%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>>[OH:23][CH:20]1[CH2:21][CH2:22][N:18]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:19]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: OC1CCNC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Yield: 50 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and rac-3-pyrrolidinol. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a light brown foam (yield 50%). MS (m/e): 328.1 (M+H+, 100%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][CH2:2][C@@H:3]([CH3:4])[N:5]=3)=[CH:12][CH:11]=2)[CH:14]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[N:22][CH:21]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
N-[(1R)-2-Hydroxy-1-methylethyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.94 g, 3.85 mmol) synthesized in Example (84a) was dissolved in tetrahydrofuran (35 mL), and anhydrous methanesulfonic acid (1.38 g, 7.70 mmol) and triethylamine (2.15 mL, 15.41 mmol) were added, followed by stirring at 50° C. for 1.5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-75%) to afford the desired compound (1.59 g, yield 85%) as a white solid.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[C:31](C#N)=[CH:30][C:29]([N+:34]([O-:36])=[O:35])=[C:28]([NH2:37])[N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:34]([O-:36])=[O:35])=[C:28]([NH2:37])[N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)nc1Cl
Product: CN(CCNc1ccc([N+](=O)[O-])c(N)n1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-6-amino-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl{2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][C:18]3[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][C:18]3[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3c(F)cccc32)c1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(CC2c3ccccc3CCc3c(F)cccc32)c1
Reaction time: 18 h
Yield: 4 %

Procedure:
Dissolve 150 mg (0.38 mmol) N-[3-(1-fluoro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methanesulfonamide in EtOH (5 mL) and add 10% Pd/C (50 mg). Stir for 18 h under an atmosphere of hydrogen. Filter and concentrate. Purify the crude product using column chromatography (10% EtOAc/hexane→25% EtOAc/hexane) to give 6 mg product as a colorless oil. MS (ES) 394 (M−1). HPLC shows 99% purity.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])OC)[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:22][NH:23][C:5](=[NH:8])[CH:4]([O:3][CH2:1][CH3:2])[O:9][CH2:10][CH3:11]
Reactant: CCOC(OCC)C(=N)OC
Reactant: COc1ccc(CN)cc1OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(OC)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2,2-diethoxyacetimidate (294 mg, 1.824 mmol), (3,4-dimethoxyphenyl)methanamine (312 mg, 1.866 mmol), and MeOH (1.5 mL) was heated with stirring in an oil bath at 70° C. for 2 hrs and allowed to cool to room temperature. The volatile components were removed in vacuo. The residue was carried on without further purification. LCMS RT 0.96 min, MH+=297.2, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.79-6.93 (3H, m), 4.94 (1H, s), 4.41 (2H, s), 3.84-3.90 (6H, m), 3.52-3.70 (4H, m), 1.19-1.28 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:23])[CH:18]=[CH:19][CH:20]=1)#[CH:14].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=3)=[O:23])[CH:16]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1
Temperature: 60 °C
Yield: 78.3 %

Procedure:
A mixture of methyl 6-amino-5-iodonicotinate (111 mg, 0.40 mmol), N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (144 mg, 0.60 mmol), triethylamine (0.167 ml, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.032 mmol) and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.2 ml DMF at room temperature was degassed using vacuum and a balloon of H2, then copper(I)iodide (3.8 mg, 0.020 mmol) added. The reaction was heated at 60° C. for 1 hour 40 minutes, then partitioned between EtOAc and dilute brine. The EtOAc layer was dried with anhydrous Na2SO4 and rotary evaporated. The solid was recrystallized from EtOAc/hexane to give the title compound as a yellow-tan solid (122 mg, 78%).