Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Cl[C:14]1[N:15]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:17]2[S:22][C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O>[CH3:31][N:30]([CH3:32])[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:21]2[S:22][C:17]3[C:16]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:15][C:14]([N:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[C:2]4[CH3:1])=[N:19][C:18]=3[CH:20]=2)[CH2:25][CH2:26]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 12.1 %

Procedure:
A solution of 2-methylindole (0.131 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.059 g, 12%) as a light brown solid. MS m/e 491 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, J=12.43 Hz, 2H) 2.08 (t, J=10.55 Hz, 3H) 2.18 (s, 6H) 2.64 (s, 3H) 2.95 (d, J=11.30 Hz, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.42 (s, 1H) 6.98-7.20 (m, 2H) 7.37 (s, 1H) 7.43-7.56 (m, 1H) 8.03 (d, J=7.54 Hz, 1H)
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.C[O-].[Na+].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][C:20]2([C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=O)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1>C(#N)C.O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:23]2([C:20]3([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([Cl:14])=[CH:35][CH:34]=4)[CH2:22][CH2:21]3)[CH2:7][O:6]2)=[CH:32][CH:31]=1
Reactant: O=C(COc1ccc(Cl)cc1)C1(Cc2ccc(Cl)cc2)CC1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CSC
Product: Clc1ccc(CC2(C3(COc4ccc(Cl)cc4)CO3)CC2)cc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
21 g (0.17 mol) of dimethyl sulphate are added dropwise with stirring at 20° C. to a solution of 10.5 g (0.17 mol) of dimethyl sulphide in 100 ml of acetonitrile. After standing for 2 days at 20° C., 9.2 g (0.17 mol) of sodium methoxide is added to this solution, the mixture is stirred for 30 minutes at 20° C. and then 29 g (0.09 mol) of 4-chlorophenoxymethyl 1-(4-chlorobenzyl)cycloprop-1-yl ketone are added. After stirring for 16 hours at 20° C., the reaction mixture is poured into water and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 25.2 g (80% of theory) of 2-(4-chlorophenoxymethyl)-2-[(4-chlorobenzyl)cycloprop-1-yl]-oxirane are obtained in the form of a colorless oil which is employed for further synthesis without additional purification. ##STR14##
Reaction SMILES: N#N.[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[CH2:8]([Li])[CH2:9][CH2:10][CH2:11]CC.C1(O)CC1>CN1C(=O)N(C)CCC1>[CH2:5]([CH:4]1[CH2:3][CH:7]1[OH:6])[CH2:11][CH2:10][C:9]#[CH:8]
Reactant: [Li]CCCCCC
Reactant: C1CCOC1
Agent: N#N
Agent: OC1CC1
Solvent: CN1CCCN(C)C1=O
Product: C#CCCCC1CC1O
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 98 %

Procedure:
To a 2-neck 15-mL round bottomed flask equipped with a temperature probe, N2 inlet, and septum was added 1 g of 4 (7.28 mmol, 1.0 equiv) and 3.0 mL THF. The solution was cooled to an internal temperature of 0° C. with an ice bath. To this solution was added 2.95 mL of 33 wt % n-Hexyllithium (7.28 mmol, 1.0 equiv) slowly via syringe pump over 1 hour. Internal temperature rose to 6.8° C. and solution became yellow. In a separate 3-neck 100-mL round bottomed flask equipped with a temperature probe, N2 inlet, and septum 0.82 g of lithium acetylide-ethylenediamine complex (8.01 mmol, 1.1 equiv) was slurried in 5.0 mL of DMPU at room temperature. To this room temperature slurry, the cold solution of the deprotonated cyclopropanol was transferred via cannula over 5 min. After the addition, the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion was observed by GC. The brown mixture was cooled with an ice bath to 3° C. and then the ice bath was removed to prevent freezing. To this was slowly added 17.5 mL of 0.5 N HCl and an ice bath was applied to maintain an internal temperature below 21° C. The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel and removal of the aqueous layer. The aqueous layer was extracted once with 15 mL MTBE and then the combined organic layers were washed with 20 mL water followed by 20 mL brine. The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %, 98% yield). 1H NMR (400 MHz, CDCl3) δ 3.24 (dt, 1H, J=2.6, 5.3 Hz), 2.25 (dt, 2H, J=2.6, 7.6 Hz), 1.96 (t, 1H, J=2.6 Hz), 1.92 (s, 1H, OH), 1.64 (pent, 2H, J=7.3 Hz), 1.38 (sext, 1H, J=6.9 Hz), 1.24 (sext, 1H, J=6.9 Hz), 0.93 (m, 1H), 0.72 (m, 1H), 0.35 (q, 1H, J=6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 84.49, 68.37, 52.45, 30.50, 27.74, 20.17, 18.01, 14.25; GC: HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet. 5 min @ 50° C., ramp 25° C./min to 250° C. then hold for 4 min, tr(4)=7.15 min, tr(rac-5)=6.72 min.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[CH2:31]([O:33]C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1)[CH3:32].NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([O:33][CH2:31][CH3:32])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CCOc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CCOc1cc2c3ccccc3c(CNC(C)(CO)COS(C)(=O)=O)cc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1C, 12-ethoxy-6-chrysenecarbaldehyde (17A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 202°-204° (dec) (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[I-:25].[Na+].Cl>CN(C)C=O.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([I:25])[CH:19]=1
Reactant: [I-]
Reactant: Oc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(F)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
Chloramine-T trihydrate (50 g, 178 mmol) was added to a stirred, cooled (0° C.) solution of 4-fluorophenol (20 g, 178 mmol) and sodium iodide (26.7 g, 178 mmol) in dimethylformamide (250 mL). The mixture was stirred at 0° C. for 1 h., and poured into water (1000 mL). The mixture was acidified with hydrochloric acid (1M) and extracted with ether (4×200 mL). The combined organic fractions were washed with aqueous sodium thiosulfate (5%, 3×100 mL), water (2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The reside was purified by flash column chromatography on silica gel, eluting with hexane/CH2Cl2 to give the title compound as an off-white solid (7.8 g, 18%). 1H NMR (360 MHz, CDCl3) δ 5.08 (1H, s), 6.90-7.01 (2H, m), and 7.37 (1H, dd, J 7.6, 2.9 Hz).
Reaction SMILES: FC(F)(F)C1C=CC(CCC=O)=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][CH:36]=[O:37])[CH:31]=[CH:32][CH:33]=1>>[F:26][C:27]([F:38])([F:39])[C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][OH:37])[CH:31]=[CH:32][CH:33]=1
Reactant: O=CCCc1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=CCCc1ccc(C(F)(F)F)cc1
Agent: c1cc[nH+]cc1
Product: OCCCc1cccc(C(F)(F)F)c1
Yield: 229.7 %

Procedure:
According to the procedure described above for the preparation of 3-(4-trifluoromethyl-phenyl)-propionaldehyde by PCC-oxidation, 132 mg (44%) of 3-(3-trifluoromethyl-phenyl)-propionaldehyde {LC-MS: tR=0.89 min; [M+H]+=no ionization} was obtained from 3-(3-trifluoromethyl-phenyl)-propan-1-ol (300 mg, 1.5 mmol).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[C:41]3[C:36](=[C:37]([Cl:43])[CH:38]=[C:39]([Cl:42])[CH:40]=3)[CH2:35][N:34]([CH3:44])[CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[Cl:42][C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([Cl:43])[CH:38]=1)[CH2:35][N:34]([CH3:44])[CH2:33][CH:32]2[C:29]1[CH:28]=[CH:27][C:26]([S:23]([NH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[C:41]5[C:36](=[C:37]([Cl:43])[CH:38]=[C:39]([Cl:42])[CH:40]=5)[CH2:35][N:34]([CH3:44])[CH2:33]4)=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:12])=[CH:10][CH:9]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCNS(=O)(=O)c4ccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)cc4)cc3)cc2)C1
Yield: 12.7 %

Procedure:
Compound 231 was prepared following the procedure outlined in Example 215 using terephthalic acid (11.4 mg, 0.0684 mmol) and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(2-(2-(2-hydroxyethoxy)ethoxy)-ethyl)benzenesulfonamide (Compound 175.1, 100 mg, 0.136 mmol). Purification by preparative HPLC gave the title compound (9.8 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.86-7.85 (m, 9H), 7.83 (s, 2H), 7.50 (s, 1H), 7.41 (d, 4H), 6.80 (s, 1H), 3.68-3.42 (m, 26H), 3.34 (m, 2H), 3.09-3.01 (m, 12H). MS (m/z): 1135.07 [M+H]+.
Reaction SMILES: O[C@H]1CCCC[C@@H]1[N:8]1[CH2:16][C:15]2[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]([CH2:21][C:22]3[CH:23]=[N:24][C:25](SC)=[CH:26][CH:27]=3)=[CH:11][C:10]=2[C:9]1=[O:30].N[C@H]1CCCC[C@@H:33]1[OH:38].ClCC1C=CC(SC)=NC=1>>[CH3:33][O:38][C:25]1[N:24]=[CH:23][C:22]([CH2:21][C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]3[CH2:16][NH:8][C:9](=[O:30])[C:10]=3[CH:11]=2)=[CH:27][CH:26]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CSc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Agent: CSc1ccc(CCl)cn1
Product: COc1ccc(Cc2cc3c(c4ccccc24)CNC3=O)cn1

Procedure:
5-[(6-Methoxypyridin-3-yl)methyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 2-[(1S,2S)-2-hydroxycyclohexyl]-5-{[6-(methylthio)pyridine-3-yl]methyl}-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 10, substituting ammonium hydroxide for (1S,2S)-2-aminocyclohexanol, and substituting 5-(chloromethyl)-2-methoxypyridine for 5-(chloromethyl)-2-(methylthio)pyridine.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])([O:5][CH3:6])=[O:4].C(OC(=O)CCN)(C)(C)C.[C:36]([CH2:38][CH2:39][N:40]1[C:44]([CH2:45][CH2:46][NH2:47])=[N:43][N:42]=[N:41]1)#[N:37]>>[CH3:6][O:5][P:3]([CH2:7][NH:8][CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:10]([N:41]1[NH:42][N:43]=[C:44]([CH2:45][CH2:46][NH2:47])[N:40]1[CH2:39][CH2:38][C:36]#[N:37])=[O:11])([O:2][CH3:1])=[O:4]
Reactant: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Reactant: N#CCCn1nnnc1CCN
Agent: CC(C)(C)OC(=O)CCN
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)N1NN=C(CCN)N1CCC#N)OC

Procedure:
(S)-2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionic acid is treated (under conditions described in example 2 for the condensation with β-alanine t-butyl ester) with 1-(2-cyanoethyl)-5-(2-aminoethyl)tetrazole to yield (S)-5-[N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)propionyl[-2-aminoethyl]-1-(2-cyanoethyl)-tetrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.O[N:28]=[C:29]([NH2:40])[C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:40]=[C:29]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=4)[N:28]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: COc1cc(OC)cc(C(N)=NO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2noc(-c3ccc(-n4nc(-c5c(F)cccc5Cl)[nH]c4=O)cc3OC)n2)c1
Yield: 11 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), N′-hydroxy-3,5-dimethoxybenzimidamide (Intermediate-20, 0.077 g, 0.529 mmol), sodium hydride (0.006 g, 0.39 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1HNMR (DMSO-d6): δ 3.84 (s, 6H), 3.99 (s, 3H), 6.73 (s, 1H), 7.19 (s, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.67 (t, J=8.7 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.93 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 12.61 (br s, 1H); MS (m/z): 523.89 [M+]+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH2:23][CH2:24][OH:25])[CH:16]=1.[OH-].[NH4+]>ClCCl.O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH2:23][CH2:24][O:25][CH2:10][O:11][CH3:12])[CH:16]=1
Reactant: COCCl
Reactant: COc1ccc(Br)cc1CCO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOCCc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 3.33 h

Procedure:
1.48 g of N-ethyl-diisopropylamine and 0.49 g of chlorodimethyl ether are added at room temperature to a solution of 948 mg of 4-bromo-2-(2-hydroxyethyl)-anisole in 30 ml of dichloromethane. The reaction mixture is stirred for 200 minutes at room temperature, and then 1 ml of water and 1 ml of 25% ammonium hydroxide solution are added thereto. The two-phase mixture is stirred vigorously for a further 15 minutes and then the organic phase is separated off, dried over sodium sulfate and concentrated by evaporation. Purification of the residue by means of FC (hexane/dichloromethane=1:1) yields the title compound: Rf (dichloromethane)=0.6; HPLC Rt =17.33 minutes.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:27]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
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: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 80.9 %

Procedure:
A solution of 476 mg (1.0 mmol) of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole, from Example 14 step (i), in dioxane (3 ml, degassed by sonication and bubbling argon), Pd(PPh3)4 (23 mg, 0.05 mmol), phenylboronic acid (362 mg, 2.5 mmol), and Na2CO3 (1.25 ml of a 2M aqueous solution, degassed as above) was heated at 90° C. for 2 h. The solution was then diluted with ethyl acetate (100 ml) and washed with brine (2×20 ml). The organic layer was dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel chromatography gave of 6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a brown oil (345 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, 1H, J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=7.0 Hz), 7.64-7.58 (m, 2H), 7.56-751 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 (m, 1H), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3 Hz), 1.12 (t, 2H, J=8.3 Hz).
Reaction SMILES: Cl.[N:2]([O-])=O.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C.[Na+].[C:18](#[N:22])[CH2:19][C:20]#[N:21]>O.C(O)C>[C:7]1([N:6]=[N:2][CH:19]([C:18]#[N:22])[C:20]#[N:21])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: N#CCC#N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)N=Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Conc. hydrochloric acid (17.84 ml) and then a solution of 7.409 g (107.377 mmol) of sodium nitrite in water (18 ml) were added dropwise to 10.00 g (107.377 mmol) of aniline and ice (32 g) in an ice bath between 0° C. and 5° C., and the mixture was stirred at 0° C. for 30 min. At 0° C., a solution of 11.099 g (135.296 mmol) of sodium acetate in water (75 ml) was then added, and a solution of 7.049 g (107.377 mmol) of malononitrile in ethanol (6.5 ml) was subsequently added dropwise with stirring. After 2 h at 0° C., the resulting precipitate was filtered off with suction and washed with water (107 ml).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:23])[CH2:2]1.[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:34]2[O:35][CH2:36][O:37][C:31](=[CH:32][CH:33]=2)[CH:30]=1>>[ClH:24].[CH2:36]1[O:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][N:9]4[CH2:18][CH2:17][C:16]5[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=5)[C:10]4=[O:23])[CH2:2]3)=[CH:30][C:31]=2[O:37]1
Reactant: ClCCCOc1cc2ccc1OCO2
Reactant: COc1cc2c(cc1OC)C(=O)N(CCC1CCCNC1)CC2
Product: COc1cc2c(cc1OC)C(=O)N(CCC1CCCN(CCCOc3ccc4c(c3)OCO4)C1)CC2
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-ethyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3,6-methylenedioxy-phenoxy)-propane analogously to Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:24](=[O:25])[C:23]5[CH:27]=[CH:28][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-n3ncc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc43)cc2)cc1

Procedure:
Compound 373 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-dimethylaminobenzoate. 1H NMR (500 MHz, Acetone-d6) δ 9.44 (s, 1H), 9.38 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.08 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 4H), 7.81 (m, 2H), 7.76 (d, J=9 Hz, 2H), 6.79 (d, J=9 Hz, 4H), 3.06 (s, 6H), 3.05 (s, 6H).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:14][C:13]=1[CH3:21])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[SH2:29]>C(O)C>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:14][C:13]=1[CH3:21])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[S:29])[NH2:2]
Reactant: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1cccs1
Reactant: S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C(N)=S)c1cccs1
Yield: 88 %

Procedure:
0.72g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (12) was dissolved in 10ml of ethanol and then 0.63ml of triethylamine was added thereto. The reaction solution was stirred under reflux for 8 hours while introducing hydrogen sulfide gas. After removing the solvent, water was added to the residue and then the solid product which is not dissolved in water was filtered. The filtered solid product was washed with diethylether and then dried to obtain 0.70g (Yield 88%) of the title compound.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19][CH:18]=[CH:17][CH:16]=2.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:21]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:1]1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3cccnc3c21
Yield: 21.3 %

Procedure:
Triethylorthoformate (2.8 mL, 16.6 mmol) was added to a solution of 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (5.0 g, 15.1 mmol) in toluene (150 mL). The reaction was heated at reflux overnight with ethanol being collected in a Dean Stark trap. The reaction mixture was heated at reflux for an additional 6 hours and then p-toluenesulfonic acid (1.4 g, 7.5 mmol) was added and the reaction was refluxed overnight. A dark orange/brown oil had formed. The toluene supernatant was decanted off and concentrated under vacuum to provide 1.1 g of 1,1-dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The oil was identified as 4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine. This material was reacted with 1,1-dimethylethyl-dicarbonate to provide an additional 1 g of 1,1-dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The two lots were combined and carried on to the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2ncoc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2ncoc2cc1-c1ccc(NC(=O)c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 5-(5-methylbenzoxazol-6-yl)-2-pyridylamine (44) (26.6 mg, 0.12 mmol) in 2 ml DCM was added 2-fluorobenzoyl chloride (29 μl, 0.24 mmol) followed by addition of DIEA (105 μl). The resulting brown solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (180 μl) at r.t. for 40 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 24.1 mg N-[5-(5-methylbenzoxazol-6-yl)(2-pyridyl)](2-fluorophenyl)carboxamide (45) as off-white solid. (yield: 57.8%, purity>95%).