Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.C([O:14][C:15]([C:17]1[S:21][C:20](Cl)=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])C>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([C:20]3[S:21][C:17]([C:15]([OH:16])=[O:14])=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Product: Cc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)O)s3)c2cc1C

Procedure:
2-(5,6-Dimethylbenzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid was prepared in a similar manner as that for Example 1 starting with the reaction of 5,6-dimethylbenzoimidazole and 2-Chloro-4-phenylthiazole-5-carboxylic acid ethyl ester. 1H-NMR(DMSO-D6) 8.82 (s, 1H); 7.98 (s, 1H); 7.82-7.92 (m, 2H); 7.58 (s, 1H); 7.42-7.52 (m, 3H); 2.39 (s, 3H); 2.38 (s, 3H). MS M/z 350 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18]O)[CH3:16])[C:9]=2[C:8](=[O:32])[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]1=[O:39].[OH:45][CH2:46][CH2:47][C:48]1[NH:49][CH:50]=[CH:51][N:52]=1>>[F:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][N:49]3[CH:50]=[CH:51][N:52]=[C:48]3[CH2:47][CH2:46][OH:45])[CH3:16])[C:9]=2[C:8](=[O:32])[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]1=[O:39]
Reactant: OCCc1ncc[nH]1
Reactant: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCO)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Product: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCn2ccnc2CCO)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 14.8 %

Procedure:
The similar reaction to that of Example 120 was performed using N-(4-(1-(2,6-difluorobenzyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-ethylurea (135 mg, 0.218 mmol) and 2-(2-hydroxyethyl)imidazole (122 mg, 1.09 mmol) to give the title compound (23 mg, 15%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5]C(C1C(C)=CC=CC=1Cl)=O.O[C:25]1C=C(CC(O)=O)C=CC=1>>[CH3:25][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:16][C@@H:4]([C:3]([OH:2])=[O:23])[NH2:5]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(C)cccc1Cl
Product: Cc1cccc(C[C@H](N)C(=O)O)c1

Procedure:
N-[1-(2-Chloro-6-methylphenyl)carbonyl]-4-[[2-(3-hydroxphenyl))-1-oxoethyl]amino]-3-methyl-L-phenylalanine was prepared using the general procedure described in example 120 from 4-amino-3-methyl-N-[[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (79.5 mg) and 2-(3-hydroxyphenyl)acetic acid (30 mg 0.2 mmol) to give 23 mg of a colorless glass. HR MS (C26H25N2O5Cl): Obs. Mass 481.1527. Calcd. Mass 481.1530 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].Br[CH:38]([CH3:40])[CH3:39]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH:38]([CH3:40])[CH3:39])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-isopropoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 5 equivalents of sodium hydride and 4 equivalents of 2-bromopropane according to general procedure H.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([P:23](Cl)(Cl)=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(Cl)Cl>[CH2:15]([P:23]1(=[O:24])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCP(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCP1(=O)c2ccccc2CN1c1ccccc1
Yield: 5 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and octyl phosphonic dichloride. The reaction of the dilithio compound and the octyl phosphonic dichloride was conducted at -65° C. The crude product produced as a result of the chromatographic separation was dissolved in methylene chloride and separated on a Woelm's neutral alumina column using ethyl acetate as the eluant to yield 1-octyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.1 g, 5% yield) as a pale yellow oil (nD =1.5502).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c([C@@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC[C@@H](c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-[(3R)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (107 mg, 0.25 mmol), N,N-dimethylglycine (31 mg, 0.30 mmol), EDCl (53 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and N,N-diisopropylethylamine (132 μL, 0.76 mmol) in DMF (2.3 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 35 mg (27%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.27-7.39 (m, 5 H), 7.14 (d, 1 H), 6.64 (d, 1 H), 5.65 (s, 2 H), 3.95-4.97(m, 2 H), 2.62-3.32 (m, 5 H), 2.03-2.23 (m, 7 H), 1.68-1.91 (m, 2 H), 1.37-1.64 (m, 1 H); ES-MS m/z 509.15 [M+H]+, HPLC RT (min) 2.22.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]3([O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]3)[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[NH:24][CH2:23]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Cu]I>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C:2]1[C:11]3[CH2:10][CH2:9][CH2:8][C:7]4([O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]4)[C:6]=3[CH:5]=[N:4][CH:3]=1)[CH2:23]2
Reactant: CC1(C)COC2(CCCc3c(Br)cncc32)OC1
Reactant: O=C1NCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)COC2(CCCc3c(N4Cc5cc(Cl)ccc5C4=O)cncc32)OC1
Temperature: 150 °C
Yield: 86.2 %

Procedure:
A mixture of 4′-bromo-5,5-dimethyl-6′,7′-dihydro-5′H-spiro[1,3-dioxane-2,8′-isoquinoline](5.0 g, 16 mmol), 5-chloro-2,3-dihydro-isoindol-1-one (2.7 g, 16 mmol), (+)-(1S,1S)-1,2-diaminocyclohexane (0.576 mL, 4.8 mmol), copper (I) iodide (456 mg, 2.4 mmol) and Cs2CO3 (10.4 g, 32 mmol) in dioxane (80 mL) was heated at 150° C. for 4 hours. After cooling to room temperature, it was diluted with water (50 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product (5.5 g, 86%) as light yellow solid. MS: 399.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C=O.[C:35](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:28][CH2:29][N:30]([CH3:35])[CH2:31][CH2:32]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
To a mixture of 0.030 g (0.06 mmole) of 4-(3-chloro-phenyl)-2-[6-(piperidin-4-ylmethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.23), 0.0095 mL (0.13 mmole) of 37% aqueous formaldehyde solution, 0.0041 mL (0.070 mmole) of acetic acid and 2.1 mL of methanol-dichloromethane (2:5) was added 0.019 g (0.090 mmole) of sodium triacetoxyborohydride. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was diluted with dichloromethane and ethyl acetate, washed with aqueous 1M sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol-dichloromethane to give 0.015 g of 4-(3-chloro-phenyl)-2-[6-(1-methyl-piperidin-4-ylmethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.24). MH+/Z=482
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)[CH2:15][NH2:16].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCC(O)c1cccc(Br)c1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CC(C)NCC(O)c2cccc(Br)c2)cc1

Procedure:
1-(4-Methoxyphenyl)propan-2-one (3.10 g) and 2-hydroxy-2-(3-bromophenyl)ethanamine (4.08 g) were condensed and subsequently reduced with sodium borohydride (3.8 g) by an analogous procedure to that described in Example 1. The crude product was recrystallised from diethyl ether-hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-bromophenyl)ethanamine, mp 79°-83° C., as a 47:53 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30]C(=O)C)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])[CH:5]=[CH:4][N:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(Cl)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccnc(Cl)c3)c2)=C(C)C1=O
Yield: 79.1 %

Procedure:
N-(2-Chloropyridin-4-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.079 g, 0.163 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.057 g, 0.129 mmol, 79%).
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[Cl:5][C:6]1[C:14]([CH3:15])=[N:13][C:12]2[N:8]([N:9]=[C:10]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:20])[CH2:16][C:11]3=2)[C:7]=1[CH3:35].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:5][C:6]1[C:14]([CH3:15])=[N:13][C:12]2[N:8]([N:9]=[C:10]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH:29]4[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][F:4])[CH2:31][CH2:30]4)=[O:20])[CH2:16][C:11]3=2)[C:7]=1[CH3:35]
Reactant: FCCBr
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(CCF)CC1)C3
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-Bromo-2-fluoro-ethane (19 mg; 0.15 mmol; 1.1 eq.) was added to a suspension of Example 64 (60 mg; 0.14 mmol; 1 eq.) and NaHCO3 (114 mg; 1.35 mmol; 10 eq.) in DMF (2 mL) and the reaction mixture was stirred at 100° C. (MW heating) for 30 minutes. 1-Bromo-2-fluoro-ethane (9 mg; 0.07 mmol; 0.5 eq.) was added and the reaction mixture was stirred at 100° C. (MW heating) for 30 minutes. The precipitate was filtered off and the mother liquor was concentrated in vacuo. The residue was diluted with DCM, washed with 1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (5% to 20% MeOH in DCM) followed by crystallization from EA afforded the title compound (33 mg, 49%) as yellow solid. 1H NMR (CDCl3) δ 7.40-7.28 (m, 1H), 6.84-6.61 (m, 2H), 5.11-4.90 (m, 2H), 4.66 (br s, 2H), 4.56 (t, J=4.9 Hz, 1H), 4.46-4.29 (m, 2H), 2.91 (s, 1.8H), 2.86 (s, 1.2H), 2.73-2.48 (m, 7H), 2.47-2.30 (m, 2H), 2.07-1.91 (m, 2H), 1.91-1.73 (m, 2H). HPLC (max plot) 98.5%, Rt 2.96 min. UPLC/MS: (MS+) 490.3 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 13 (300 mg, 0.70 mmol) is treated with acid chloride 8 (214 mg, 0.80 mmol) using Method D to afford the title compound.
Reaction SMILES: [C:1]([C:3]([O:6][N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])([CH3:5])[CH3:4])#[N:2].N(C(C)(C)C#N)=N[C:21](C)([CH3:24])[C:22]#N>>[C:1]([C:3]([O:6][N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH2:12][CH2:22][CH2:21][CH3:24])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNC(=O)C(C)(C)N(OC(C)(C)C#N)C(C)(C)C
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCNC(=O)C(C)(C)N(OC(C)(C)C#N)C(C)(C)C
Yield: 48 %

Procedure:
The compound is prepared in analogy to compound (201) from the nitroxide (103) and azobisisobutyronitrile in 48% yield as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].Cl.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:15][CH2:16]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-nitrobenzoyl chloride (10.0 g, 53.9 mmol) in DCM (10 ml) was added piperidin-4-one hydrochloride (10.96 g, 81.0 mmol) and triethylamine (22.53 ml, 162.0 mmol). The reaction mixture was stirred at room temperature for 30 min and evaporated to dryness. The crude material was treated with diethyl ether, solid obtained was filtered and dried under vacuum to give the title compound (9.0 gm).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=Cc1cc(O)cc(OCc2ccccc2)c1

Procedure:
Preparation takes place in analogy to Example 3H from 5.0 g (36.2 mmol) of 3,5-dihydroxybenzaldehyde, 6.81 g (39.8 mmol) of benzyl bromide and 11.8 g (36.2 mmol) of cesium carbonate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[CH:10]2)=[O:4].O.[H][H]>C(O)(=O)C.[Pt]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[NH:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)c(F)c2ccc(C)nc12
Agent: [Pt]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c(F)c2c1NC(C)CC2
Yield: 68.9 %

Procedure:
A solution of 8.0 g (33.7 mmol) of 5,6-difluoro-2-methylquinoline-8-carboxylic acid methyl ester (Example 33) in 100 mL of glacial acetic acid is treated with 2.15 g of platinum on carbon (0.8 g of active catalyst+62.8% water) and then shaken in a hydrogen atmosphere at temperatures of 24° C. to 29° C. and pressures of 23.9 to 46.6 psi for 3 hours. The catalyst is removed by filtration and the solvent is removed in vacuo at 50° C. The residue is triturated with water (50 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers are stirred with 5% sodium bicarbonate solution, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane to give 5.6 g of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): 7.66 (bs, 1H), 7.49 (m, 1H), 3.82 (s, 3H), 3.46 (m, 1H), 2.88 (m, 1H), 2.67 (m, 1H), 1.97 (m, 1H), 1.27 (d, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:18]S(C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)(C(C)(C)C)(C)C.[ClH:25]>CO>[ClH:25].[NH2:18][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)[CH2:9][OH:8]
Reactant: CC(C)(C)S(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: CO
Product: N[C@@H](CO)c1ccc(F)cn1
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of (RS)—N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide (Intermediate 22, 1.13 g, 3.02 mmol) in MeOH (15 ml) was added hydrochloric acid (4 M in dioxane, 3.02 ml, 12.08 mol) at 0° C. and the mixture was stirred for 15 minutes and was concentrated. The mixture was triturated from hexanes to provide the title salt (575 mg). The product is highly hygroscopic. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (s, 1H) 8.55 (s, 2H) 7.76-7.93 (m, 1H) 7.65 (dd, J=8.29, 4.52 Hz, 1H) 4.43 (d, J=4.52 Hz, 1H) 3.77 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=O)[CH:27]=[N:28][CH:29]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:32][S:33]([CH2:36][CH2:37][NH:38][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:13][CH:12]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:29]=[N:28][CH:27]=1)(=[O:35])=[O:34]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(C=O)c5)n4n3)cc2)CC1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
Into a 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-pyridine-3-carbaldehyde (100.2 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-pyridin-3-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (8 mg, 6%). LCMS (E/I+) 521.19 (M+H). NMR 1H (DMSO-d6)-9.27 (s, 1H), 9.19 (d, 1H, J=2.25 Hz), 8.97 (s, 1H), 8.57 (t, 1H, J=1.90 Hz), 8.52 (d, 1H, J=1.61 Hz), 7.56 (d, 2H, J=8.79 Hz), 7.27 (d, 1H, J=5.28 Hz), 6.95 (d, 1H, J=5.28 Hz), 6.92 (d, 1H, J=8.79 Hz), 3.84 (d, 2H, J=5.80 Hz), 3.25 (t, 2H, J=6.63 Hz), 3.08 (t, 4H, J=4.97 Hz), 3.00 (s, 3H), 2.94 (q, 2H, J=6.63 Hz), 2.46 (t, 4H, J=4.97 Hz), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=O)[NH:9][C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[CH:11]=[CH:12][C:6]2[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=2[N:9]=1
Reactant: CSc1ncc2ccc(=O)[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc2ccc(Cl)nc2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
A suspension of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (297 mg, 1.54 mmol) in POCl3 (6 mL) was stirred under argon at 80° C. for 16 hours. The solution was cooled, and the resulting precipitate was filtered and washed with EtOAc to afford the title compound (43 mg, 13%). The filtrate was diluted with EtOAc, washed with NaHCO3 and dried with Na2SO4. After removal of the solvent, a second crop was obtained (154 mg, 48%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(CCOCc2ccccc2)CC1
Yield: 97 %

Procedure:
8-(2-Benzyloxy-ethyl)-1,4-dioxa-spiro[4.5]decane (Intermediate R1, 1.02 g, 3.70 mmol) (obtainable as desribed in the publication by Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016, incorporated herein by reference) was dissolved in acetone (100 mL): H2O (5 mL) and reacted with TsOH (140 mg, 0.74 mmol) at 45° C. for 5 h. After a standard aqueous work-up the material was purified by chromatography on SiO2 to give 4-(2-benzyloxy-ethyl)-cyclohexanone as a colorless oil (97%).