Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[C:14]1([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][N:24]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzoyl isocyanate (1.5 grams) in a small amount of dichloromethane was added to a solution of 5-phenyl-2-pyridylamine (1.0 gram) in 15 ml dichloromethane. After refluxing for about 5 minutes a precipitate formed. Following this, the reaction mixture was stirred at room temperature, cooled, and then the precipitate was filtered and recrystallized from ethanol, yield 1.8 grams. The identity of the final product was confirmed by NMR, m.p. 221°-231° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7]2)[CH2:4]1.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:23][CH2:24][CH2:25][C:26]([NH:2][CH:3]1[CH2:4][CH:5]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)=[O:27]
Reactant: O=C(Cl)CCCl
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCCl)C3)c2ccccc12

Procedure:
This compound was synthesized in the same way as 165RL23 using 165RL21 (320 mg, 1.15 mmol), 3-chloropropionyl chloride (120 μL, 1.27 mmol), DIPEA (220 μL, 1.27 mmol) and DMF (10 mL). The crude product was purified by column chromatography using ethyl acetate/MeOH (95:5) to give the title compound (318 mg, 75
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:23][O:24][CH:25]([O:43][CH3:44])[C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1>ClCCCl>[CH:1]1([CH2:7][NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][C:28]3[CH:37]=[CH:38][C:39]([N+:40]([O-:42])=[O:41])=[C:26]([CH:25]([O:24][CH3:23])[O:43][CH3:44])[CH:27]=3)[CH:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(OC)c1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction was completed under N2. Cyclohexanecarboxaldehyde (0.01 mol) and then NaBH(OAc)3 (0.015 mol) were added to a solution of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.01 mol) in DCE (130 mL). The reaction mixture was stirred overnight at room temperature and washed with a saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH:1]1([CH:4]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[O:5][C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][C:12]3[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:29][CH3:30])[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH:1]1([CH:4]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[O:5][C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][C:12]3[C:17]([NH2:18])=[CH:16][C:15]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:29][CH3:30])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3[N+](=O)[O-])cc2OC)C2CC2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3N)cc2OC)C2CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a stirred solution of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (1.10 g, 2.13 mmol) and ammonium chloride (0.564 g, 10.54 mmol) in ethanol (8 mL) and water (2 mL) was added iron powder (0.596 g, 10.67 mmol). The mixture was heated to 80° C. After 2 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. Chromatographic purification of the residue (neutral alumina, 2% methanol in dichloromethane elute) afforded 0.984 g (95%) of N2-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)[CH:7]=[C:6]2[CH:18]=[O:19].[I-:20].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][I:20])[CH:7]=[C:6]2[CH:18]=[O:19]
Reactant: COc1ccc2c(c1)c(C=O)cn2CCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)c(C=O)cn2CCCCCI
Temperature: 25 °C

Procedure:
A stirred solution of 5-methoxy-1-(5-chloropentyl)indole-3-carboxaldehyde and sodium iodide in acetonitrile under argon is heated under reflux for 18 h, cooled to room temperature and partitioned between ether and water. The combined organic extracts are washed (aqueous sodium metabisulfite solution, water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=[O:38].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][C@@H:17]5[O:38][C@@:18]65[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]6)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3C[C@@H]4O[C@@]45CCCC[C@@H]5[C@H]32)cc1
Temperature: 0 °C
Reaction time: 168 h

Procedure:
20 g of the diketal prepared in Example 1 c) are dissolved in 200 ml of methylene chloride. 0.1 ml of pyridine are added, the whole is cooled to 0° C., and 0.9 ml of hexachloroacetone is added. 9.2 ml of a 30% aqueous hydrogen peroxide solution are then added dropwise. The whole is stirred at room temperature for 7 days and then saturated sodium thiosulphate solution is cautiously added to the reaction solution with gentle cooling. The aqueous phase is removed and extracted repeatedly with methylene chloride and the organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The crude product is purified by chromatography on silica gel with a mixture of ethyl acetate and hexane. 16.6 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5α,6α-epoxy-oestrane are obtained in the form of a white foam.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH2:11][OH:12])[CH:9]=[CH2:10].C(N(CC)CC)C.[CH3:20][C:21](OC(C)=O)=[O:22]>CN(C1C=CN=CC=1)C.CCOCC>[C:21]([O:12][CH2:11][C:3]1([CH:9]=[CH2:10])[CH2:4][CH2:5][C:6]([CH3:8])=[CH:7][CH:2]1[CH3:1])(=[O:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC1(CO)CCC(C)=CC1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC1(COC(C)=O)CCC(C)=CC1C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
To a solution of (2,4-dimethyl-1-vinylcyclohex-3-enyl)methanol (3.50 g, 21.1 mmol), triethylamine (3.83 g, 38 mmol) and a catalytic amount of DMAP in Et2O (30 ml) was added Ac2O (3.22 g, 31.6 mmol). The mixture was stirred for 5 h, poured on water and extracted with Et2O. The combined organic layers were washed with water and brine, dried and evaporated in vacuo. The residue was distilled bulb-to-bulb to yield (2,4-dimethyl-1-vinylcyclohex-3-enyl)methyl acetate (3.81 g, 86%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][S:4][C:3]=1[C:14]([O-:16])=O.[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[NH2:34])=[CH:21][CH:20]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[NH:34][C:14]([C:3]2[S:4][CH:5]=[C:6]([CH2:7][N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[C:2]=2[Cl:1])=[O:16])=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C([O-])c1scc(CN2CCOCC2)c1Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CN2CCOCC2)c1Cl
Reaction time: 0.75 h
Yield: 16 %

Procedure:
To a mixture of sodium 3-chloro-4-(morpholin-4-yl)methyl-2-thiophene carboxylate (1.0 g, 3.9 mmol) and N-(4-chlorophenyl)-2-amino-5-chlorobenzamide (0.88 g, 3.1 mmol) in pyridine (20 mL) at −10° C. was added POCl3 (0.40 mL, 4.3 mmol). After 45 minutes, the mixture was poured onto ice-water and the resulting solid collected by filtration. Crystallization from 1-butanol afforded 0.26 g (13% yield) of N-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (d, 2), 7.4 (d, 3), 3.6 (s, 2), 3.3 (br, 4), 2.4 (br, 4) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Br[CH2:26][CH2:27][CH3:28]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CCCBr
Product: CCCN(c1c(C)cc(C)cc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Yield: 88.3 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.295 g (2.4 mmol) of 1-bromopropane provided 0.691 g (88%) of the desired product as a yellow gum after preparative TLC eluting with 1:3 EtOAc:hexane. Electrospray Mass Spec 392.2(M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]=[C:6]([SH:8])[S:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]3[O:35][CH2:34]3)[C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]([OH:35])[CH2:34][S:8][C:6]3[S:5][N:4]=[C:3]([S:2][CH3:1])[N:7]=3)[C:28]([OH:30])=[O:29])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: CSc1nsc(S)n1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc(SC)ns3)C(=O)O)cc2)cc1

Procedure:
Example 38 is prepared from 3-methylmercapto-5-mercapto-1,2,4-thiadiazole and 1d using the procedure described for compound 20.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>CS(C)=O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Reaction time: 39 h
Yield: 99.9 %

Procedure:
To a suspension of D-allo-threonine (4.30 g, 36.1 mmol) and K2CO3 (8.73 g, 63.2 mmol) in DMSO (50 mL) was added 4-fluoro-2-(trifluoromethyl)benzonitrile (5.69 g, 30.1 mmol) at room temperature. The reaction mixture was heated to 75° C. and stirred for 39 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (400 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a brown oil (8.67 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.69 (d, J=8.6 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.07 (dd, J=2.5, 8.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.35 (dd, J=4.9, 8.4 Hz, 1H), 4.29 (dq, J=4.9, 6.5 Hz, 1H), 1.32 (d, J=6.4 Hz, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[CH2:6][CH2:5]1)(=O)C.Cl>CO.O>[N+:13]([C:11]1[CH:10]=[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:7]2[C:12]=1[NH:4][CH2:5][CH2:6]2)([O-:15])=[O:14]
Reactant: COC(=O)Cc1cc2c(c([N+](=O)[O-])c1)N(C(C)=O)CC2
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cc2c(c([N+](=O)[O-])c1)NCC2

Procedure:
A solution of 16 (417 mg, 1.5 mmol) in a mixture of methanol (25 mL), water (5 mL) and conc. HCl (2.5 mL) was heated under reflux for 4 h. The solution was diluted with water (7 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a viscous oil. Trituration with ether and recrystallization (Et2O-hexanes) afforded 12 as red microcrystals (255 mg, 72%), mp 113-115° C.; UV: λmax (EtOH)/nm 246 (ε/M−1cm−1 16 600), 431 (5600); λmax [EtOH-25 mM Na phosphate, pH 7.0 (1:40)]/nm 238 (ε/M−1cm−1 16 400), 289 (6060), 450 (5060); IR: νmax/cm−1 3420, 3380, 1740, 1645, 1600, 1520; 1H NMR: δH (90 MHz) 7.64 (br s, 1H), 7.16 (br s, 1H), 6.71 (br s, 1H), 3.87 (t, J=8.3 Hz, 2H), 3.69 (s, 3H), 3.51 (s, 2H) and 3.15 (t, J=8.3 Hz, 2H). Anal. Calcd for C11H12N2O4: C, 55.93; H, 5.12; N, 11.85. Found: C, 55.74; H, 5.07; N, 11.68.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+]>CCO>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of 802 mg (3.66 mmol) of methyl 3-cyano-4-isopropyloxybenzoate (from Step C) in 5.0 mL EtOH was treated with 770 μL of 5.0 N NaOH. The mixture was stirred at rt for 16 h and then concentrated. The residue was partitioned between EtOAc and aqueous HCl. The organic layer was separated, dried over Na2SO4, and concentrated to give 706 mg of the title compound: 1H NMR (500 M, CDCl3) δ 1.46 (d, J=6.0, 6H), 4.74-4.81 (m, 1H), 7.02 (d, J=9.0, 1H), 8.24 (dd, J=2.3, 8.9, 1H), 8.32 (d, J=2.0, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH:29]([CH3:33])[CH3:28])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) and pyridine (0.09 ml) in dichloromethane (3 ml) was added 2-methylpropanoyl chloride (0.1 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was washed with diisopropyl ether to give the title compound as a pale-yellow powder (0.21 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]([OH:14])[CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(C=O)COC1(C)C
Reactant: C=CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5 g (21.81 mmol) of racemate (SR)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester are dissolved in 33 ml of THF, placed under argon and cooled to −78° C. 43.62 ml (21.81 mmol) of a 0.5 M 3-butenylmagnesium bromide solution in THF are added dropwise. The mixture is stirred further at room temperature overnight. After a TLC check, about 90 ml of a saturated NH4Cl solution are added to the mixture with cooling, the mixture is stirred further overnight and diluted with about 50 ml of water. The phases are separated, and the aqueous phase is extracted a further twice with EA. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue is subjected to flash chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=1.[S-:14][C:15]#[N:16].[K+].BrBr>C(O)(=O)C.C1CCCCC1>[CH3:11][C:6]1[C:7]2[N:8]=[C:15]([NH2:16])[S:14][C:9]=2[CH:10]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=1
Reactant: N#C[S-]
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1cc(OC(F)(F)F)cc2sc(N)nc12
Yield: 71.1 %

Procedure:
The procedure is as in Example 1, starting with 4-trifluoromethoxy-2-methylaniline (0.65 g), potassium thiocyanate (1.3 g) and bromine (0.35 cc) in acetic acid (12 cc). After purification on a column of silica (200 g; particle size: 0.063-0.200 mm), eluting with a cyclohexane/ethyl acetate mixture (50:50 by volume), the white solid obtained (0.65 g) is ground in cyclohexane (20 cc), drained and dried at 60° C. under reduced pressure (1 mm Hg; 0.13 kPa), to give 4-methyl-6-trifluoromethoxy-2-benzothiazolamine (0.6 g), m.p. 162° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[O:25]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[N:22]=[C:21]([NH:23][C:26](=[O:28])[CH3:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(N)c2c1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (50 mg, 0.14 mmol, prepared in analogy to Example 59) and acetic anhydride (2 mL) was heated with stirring at 110° C. for 2 hours under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 30 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J=7.6 Hz, 1 H), 7.80 (s, 1 H), 7.56 (m, 3 H), 7.28 (m, 1 H), 7.21 (m, 1 H), 5.11 (s, 2 H), 4.48 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[N:15][CH:14]=1>[Cu]I.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.C(N(CC)CC)C>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][C:6]=2[NH2:8])[CH:16]=[N:15][CH:14]=1
Reactant: C#Cc1cncc(C(=O)OC)c1
Reactant: Nc1cc(Cl)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(C#Cc2cnc(Cl)cc2N)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A 250 mL round bottom flask flushed with N2 was charged with 2-chloro-5-iodo-pyridin-4-ylamine (1.00 g, 3.93 mmol), 5-ethynyl-nicotinic acid methyl ester (0.633 g, 3.93 mmol), copper(I) iodide (0.037 g, 0.196 mmol), bis(triphenylphosphine)palladium(II) chloride (0.138 g, 0.196 mmol) and triethyl amine (50 mL). The reaction mixture was stirred at 100° C. for 3 h. The reaction was cooled to room temperature, filtered and the precipitate washed thoroughly with ethyl acetate. The filtrate was washed with water twice. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford crude product 5-(4-amino-6-chloro-pyridin-3-ylethynyl)-nicotinic acid methyl ester as a brown solid which was taken onto next step without any purification. ESI-MS: m/z 288.0 (M+H)+
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: OCC(F)(F)F
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(OCC(F)(F)F)n4)cc3)cc12

Procedure:
Using trifluoroethanol and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 466 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[C:18]([O:20][C:21]4[C:22]([CH3:30])=[N:23][C:24]([N+:27]([O-])=O)=[CH:25][CH:26]=4)[CH:17]=[CH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:30][C:22]1[N:23]=[C:24]([NH2:27])[CH:25]=[CH:26][C:21]=1[O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)[CH:19]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Yield: 80.1 %

Procedure:
A solution of 1-methyl-4-(4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)phenyl)piperazine (0.333 g, 0.821 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% w/w water, 0.087 g, 0.082 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness to afford 6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (247 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1 H), 7.85 (d, J=8.8 Hz, 2 H), 7.21-7.20 (m, 2 H), 6.98 (d, J=8.8 Hz, 2 H), 6.57 (dd, J=5.6, 2.4 Hz, 1 H), 6.35 (d, J=8.7 Hz, 1 H), 5.94 (s, 2 H), 3.20 (t, J=4.7 Hz, 4 H), 2.45 (s, 4H), 2.22 (s, 3 H), 2.07 (s, 3H); MS (ESI) m/z: 376.2 (M+H+).