Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C/C=C(/C(N[C@H]([C@@H](O)C([O:18][C@@H:19]1[C:40]([CH3:41])=[C:39]2[C:42]([CH3:44])([CH3:43])[C@:21]([OH:59])([C@@H:22]([O:50][C:51]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:52])[C@@H:23]3[C@:28]4([O:31][C:32]([CH3:34])=[O:33])[CH2:29][O:30][C@@H:27]4[CH2:26][C@H:25]([OH:35])[C@@:24]3([CH3:49])[C:36]([C@@H:38]2[O:45][C:46]([CH3:48])=[O:47])=[O:37])[CH2:20]1)=O)C1C=CC=CC=1)=O)\C>CO>[CH3:41][C:40]1[C@@H:19]([OH:18])[CH2:20][C@:21]2([OH:59])[C:42]([CH3:43])([CH3:44])[C:39]=1[C@@H:38]([O:45][C:46]([CH3:48])=[O:47])[C:36]([C@@:24]1([CH3:49])[C@H:23]([C@@H:22]2[O:50][C:51]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[C@:28]2([O:31][C:32]([CH3:34])=[O:33])[CH2:29][O:30][C@@H:27]2[CH2:26][C@@H:25]1[OH:35])=[O:37]
Reactant: C/C=C(\C)C(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Solvent: CO
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
0.5 mg cephalomannine in 20 μl methanol was incubated with 2 ml supernatant for 17 hours on an end-over-end shaker (Fisher Roto-Rack). The solution was extracted with methylene chloride, the extract was evaporated, resuspended in methanol and analyzed by HPLC (Method 2 described following). Cephalomannine concentration was decreased from 0.175 mg/ml to 0 and 0.110 mg/ml baccatin III was produced (89 mol % yield based on analyzed initial cephalomannine concentration).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=[CH:26][C:23]=1[CH:24]([OH:25])[C:9]#[C:8][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1c(C=O)ccc([N+](=O)[O-])c1OC
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1c(C(O)C#Cc2ccccc2)ccc([N+](=O)[O-])c1OC
Yield: 91 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,3-dimethoxy-4-nitro-benzaldehyde was reacted to give the title compound as a colourless oil (1.42 g, 91%). LCMS (Method G): RT=3.66 min, [M−OH+H]+=297.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)[CH2:11][C:12]1[CH:39]=[CH:38][C:15]2[N:16]=[C:17]([NH:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:18]([CH2:19][C:20]3[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=3)[C:14]=2[CH:13]=1)(C)(C)C.Cl>O.O1CCCC1>[NH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:39]=[CH:38][C:15]2[N:16]=[C:17]([NH:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:18]([CH2:19][C:20]3[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=3)[C:14]=2[CH:13]=1)[C:40]1[CH:41]=[C:42]([CH3:47])[CH:43]=[C:44]([CH3:46])[CH:45]=1
Reactant: Cc1cc(C)cc(N(CCNC(=O)OC(C)(C)C)Cc2ccc3nc(NCCCN4CCOCC4)n(Cc4nc(C)ccc4O)c3c2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(N(CCN)Cc2ccc3nc(NCCCN4CCOCC4)n(Cc4nc(C)ccc4O)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
A mixture of (2-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester, prepared as described for compounds n-4, (0.00012 mol) in a 3N solution of HCl in water (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. The precipitate was filtered off and taken up in a 10% solution of K2CO3 in water. The solution was saturated with K2CO3 (powder) and extracted with CH2Cl2/CH3OH (95/5). The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.07 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN/CH3OH/diisopropylether, yielding 0.03 g of 2-[6-{[(2-amino-ethyl)-(3,5-dimethyl-phenyl)-amino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (Compound 66, 44%, melting point: 196° C.).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:28]([O:35][C:36](=[O:64])[C@H:37]([CH2:60][CH2:61][S:62][CH3:63])[NH:38]C(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)NC(OC(C)(C)C)=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36](=[O:64])[C@H:37]([CH2:60][CH2:61][S:62][CH3:63])[NH:38][C:11](=[O:27])[C@H:12]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Product: CSCC[C@H](NC(=O)[C@H](Cc1cccs1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-β-(2-thienyl)-L-alanine 2,4,5-trichlorophenyl ester is substituted for the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 5 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-β-(2-thienyl)-L-alanyl-L-methionine benzyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:7][C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH:14]([CH3:15])[CH3:16])=[CH:18][CH:19]=1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: NC(c1ccccc1)c1ncco1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
The crude 1-(1,3-oxazol-2-yl)-1-phenylmethanamine (0.10 g, 0.57 mmol) was mixed with 4-isopropylpheylacetic acid (0.10 g, 0.57 mmol), HOAt (0.086 g, 0.63 mmol) and EDC (0.12 g, 0.63 mmol) in DMF (1.0 mL) and stirred at room temperature for 0.5 h. Purification by reverse-phase HPLC gave the product (0.025 g, 13%). ES-MS [M+1]+: 335.1. 1H NMR (CDCl3, 400 MHz) δ 7.58 (s, 1H), 7.31-7.28 (m, 3H), 7.22-7.20 (m, 6H), 7.07 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 3.62 (s, 2H), 2.90 (m, J=6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Br)=[CH:46][C:45]=1[CH3:52]>CC#N>[Br:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]3)(=[O:14])=[O:13])=[CH:46][C:45]=1[CH3:52]
Reactant: Cc1cc(CBr)ccc1Br
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: Cc1cc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(c2)CCC(C)(C)O3)ccc1Br
Temperature: 90 °C
Yield: 68.1 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-4-(bromomethyl)-2-methylbenzene (631 mg, 2.391 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (516 mg, 68% yield). 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=2.2 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.84 (d, J=9.3 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.82 (t, J=6.7 Hz, 2HLRMS [ESI, MH+] m/z calcd for C25H33BrNO5S 538.13, found 538.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:33]=[CH:32][N:31]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccnc(OC)c3)cc2)C(=O)O1

Procedure:
(S)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following conditions analogous to those described in Example 6 using PdCl2(dppf) as catalyst. tR=2.25 min, m/z 457 (M+1). 1H NMR (CD3OD) δ 8.08 (t, 1H), 7.50-7.27 (m, 7H), 7.11 (t, 1H), 6.92 (d, 1H), 6.86 (t, 2H), 5.13 (m, 1H), 4.71 (s, 1H), 4.53 (s, 1H), 3.88 (d, 3H), 2.95 (m, 2H), 2.58 (m, 2H), 2.47 (m, 1H), 2.04 (m, 1H), 1.51-1.40 (m, 6H), 1.26 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])=[C:35]=O>ClCCl>[F:1][C:2]1[C:3]([N:14]=[C:35]=[N:34][C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=[CH:39][C:38]=2[O:47][CH3:48])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC

Procedure:
5.0 g (10.98 mmol) of methyl (2E)-3-{3-fluoro-2-[(triphenylphosphoranylidene)amino]phenyl}-2-propenoate (Example 10A) are initially charged in 50 ml of dichloromethane, and the mixture is stirred with 2.5 g (11.53 mmol) of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene (Example 17A) at room temperature overnight. The solvent is removed by distillation and the product is then purified by chromatography on silica gel (isohexane/dichloromethane 2:1; 1:1) and recrystallized from isohexane.
Reaction SMILES: C([NH:8][C@H:9]([C:11](N)=O)[CH3:10])(OC(C)(C)C)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C(Cl)Cl.CCO>[F:26][C:27]1[CH:32]=[CH:31][C:30]2[N:33]=[C:10]([C@@H:9]([NH2:8])[CH3:11])[N:34]([C:35]3[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=3)[C:29]=2[CH:28]=1
Reactant: Nc1ccc(F)cc1Nc1cncc(F)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
To a suspension of (S)-Boc-alaninamide (337 mg, 1.79 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (340 mg, 1.79 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was left to stir at RT for 1 h. The volatiles were removed under reduced pressure and to the resulting residue was added 4-fluoro-N2-(5-fluoropyridin-3-yl)-benzene-1,2-diamine (198 mg, 0.895 mmol) in absolute EtOH (5 mL) and the mixture stirred at 80° C. for 18 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried, concentrated in vacuo and the resulting residue taken up in DCM (2 mL) and TFA (1 mL) added. After stirring at RT for 1 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% MeOH in DCM) to afford the title compound as a colourless oil (52 mg, 21% over 2 steps). LCMS (Method C): RT 1.76 min [M+H]+ 275.20
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-nitrobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[H][H].C(OCC)(=O)C>[Pd].CO>[NH2:13][C:12]1[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(c1ncccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1ncccc1N)S(C)(=O)=O

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=[O:16])[C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][CH3:15])[CH2:9][CH2:8]1)C.[BH4-].[Na+]>C(O)C>[CH2:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([CH:6]([OH:16])[CH2:5][CH2:4][OH:3])[CH2:8][CH2:9]1)[CH2:14][CH3:15]
Reactant: CCC[C@H]1CC[C@H](C(=O)CC(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC[C@H]1CC[C@H](C(O)CCO)CC1
Reaction time: 5 h

Procedure:
An ethanol (300 ml) solution of (3-oxo-3-(trans-4-propyl-cyclohexyl)-propionic acid ethyl ester (3) (220.0 g) prepared in the second step was added dropwise at 50° C. or lower to a suspension of sodium borohydride (45 g) in ethanol (500 ml), in a reaction vessel under an atmosphere of nitrogen, and the stirring was continued at room temperature for 5 hours. The reaction mixture was quenched with water (1,000 ml), to which ethyl acetate (500 ml) was added to give two layers The water layer was extracted with ethyl acetate (500 ml) twice, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 500 g, eluent: heptane/ethyl acetate=50/50 by volume) to give 1-(trans-4-propyl-cyclohexyl)-propane-1,3-diol (4) (135 g) in 67% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-chloro-phenyl isocyanate (0.073 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 45 as a colorless solid (0.097 g, 54%). LCMS m/z (%)=421 M+H+ (37Cl, 53), 419 M+H+ (35Cl, 77) 1H NMR (400 MHz, CDCl3) δ: 7.689 (bs, 2H), 7.617 (s, 1H), 7.460 (d, J=2.62 Hz, 1H), 7.438 (d, J=2.52 Hz, 1H), 7.22-7.28 (m, 3H), 6.947 (d, J=8.93 Hz, 1H), 4.245 (m, 1H), 3.808 (s, 3H), 1.575 (d, J=6.35 Hz, 3H), 1.381 (d, J=6.35 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=S.IC>C(O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2N)CC1
Solvent: CCO
Solvent: CI
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Yield: 28 %

Procedure:
A mixture of 28 parts of ethyl 4-[[(2-aminophenyl)aminothioxomethyl]amino]-1-piperidinecarboxylate, 112 parts of iodomethane and 240 parts of ethanol was stirred and refluxed for 8 hours. The reaction mixture was evaporated and the residue was taken up in water. The whole was alkalized with ammonium hydroxide and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 7 parts (28%) of ethyl 4-(1H-benzimidazol-2-yl-amino)-1-piperidinecarboxylate (41).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[N:11][C:12]=2[CH:18]=1)=[O:21]
Reactant: CN
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Product: CNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1

Procedure:
Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 71.8 μl of a methylamine solution (2M in tetrahydrofuran), 14.8 mg of expected product are obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[F:29][C:30]1[C:31]([N+:41]([O-:43])=[O:42])=[C:32]([CH:37]=[C:38](F)[CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].C([O-])([O-])=O.[Na+].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:24]([C:38]3[CH:39]=[C:30]([F:29])[C:31]([N+:41]([O-:43])=[O:42])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.850 g, 4.60 mmol), methyl 3,5-difluoro-2-nitrobenzoate (1.996 g, 9.19 mmol) and Na2CO3 (1.462 g, 13.79 mmol) in hexamethylphosphoramide (25 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and filtered through a pad of Celite®. The filtrate was washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (0-35% EtOAc in hexanes) to give methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate (1.61 g, 58% yield) as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.62 (br. s., 1H), 0.79-0.95 (m, 2H), 0.96-1.11 (m, 1H), 1.84-1.97 (m, 1H), 3.01 (d, J=5.0 Hz, 3H), 3.31-3.36 (m, 3H), 3.87 (s, 3H), 5.82 (d, J=4.6 Hz, 1H), 7.22 (t, J=8.6 Hz, 2H), 7.37-7.44 (m, 1H), 7.50-7.54 (m, 2H), 7.56 (s, 1H), 7.83-7.92 (m, 2H). LCMS (m/z, ES+)=600.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][CH2:9][N:10]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 114.7 %

Procedure:
Intermediate (7a) (3.3 g, 5.2 mmol) was dissolved in DCM and cooled to 0° C. DIPEA (2.7 mL, 15.6 mmol) was added, followed by benzyl chloroformate (804 μL, 5.7 mmol). After 90 minutes, water (20 mL) was added and the mixture was extracted DCM (3×80 mL) then washed with saturated aqueous NaCl. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to afford intermediate (7b) as a white solid (4.6 g).