Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nn2ccc3c(c2c1CCN)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nn2ccc3c(c2c1CCNC(C)=O)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 2-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (110 mg, 0.476 mmol) and triethylamine (133 μL, 0.954 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (90.0 μL, 0.952 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 μL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=90/10→100/0) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (67.8 mg, yield 52%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[S:20]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: ClCc1cccnc1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Agent: Cl
Product: CC(C)N1CCC(N(Cc2cccnc2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-pyridin-3-ylmethyl-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 83 mg (1 equiv.) 3-chloromethyl-pyridine hydrochloride and 200 mg (0.50 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide (reaction temperature: 60° C.). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-pyridin-3-ylmethyl-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a light yellow amorphous material.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:17])[NH:11]2)[OH:5].C(N(CC)CC)C.[C:25]1([C@H:31]([NH:62][C:63]([O:65][C@@H:66]2[CH:71]3[CH2:72][CH2:73][N:68]([CH2:69][CH2:70]3)[CH2:67]2)=[O:64])[C:32]2[CH:33]=[C:34]([CH:59]=[CH:60][CH:61]=2)[O:35][CH2:36][C:37]2[CH:58]=[CH:57][C:40]([C:41]([N:43]3[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH2:53][CH2:54][CH:55]=O)=[O:50])[CH2:45][CH2:44]3)=[O:42])=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[C:25]1([C@H:31]([NH:62][C:63]([O:65][C@@H:66]2[CH:71]3[CH2:70][CH2:69][N:68]([CH2:73][CH2:72]3)[CH2:67]2)=[O:64])[C:32]2[CH:33]=[C:34]([CH:59]=[CH:60][CH:61]=2)[O:35][CH2:36][C:37]2[CH:58]=[CH:57][C:40]([C:41]([N:43]3[CH2:44][CH2:45][CH:46]([C:49]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:2][CH2:3][C@H:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]([OH:16])=[C:12]5[C:7]=4[CH:8]=[CH:9][C:10](=[O:17])[NH:11]5)=[O:50])[CH2:47][CH2:48]3)=[O:42])=[CH:39][CH:38]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=CCCCOC(=O)C1CCN(C(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCC(C(=O)OCCCCNC[C@H](O)c4ccc(O)c5[nH]c(=O)ccc45)CC3)cc2)c1)O[C@H]1CN2CCC1CC2
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To a suspension of (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (0.136 g, 0.53 mmol) in methanol (3.5 mL) was added triethylamine (0.148 mL, 1.06 mmol). The mixture was stirred for 10 minutes and then a solution of 4-oxobutyl 1-(4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoyl)piperidine-4-carboxylate (0.337 g, 0.50 mmol) in methanol (3.4 mL) was added. The mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (0.267 g, 1.26 mmol) followed by acetic acid (0.121 mL, 2.12 mmol) was added and the reaction continued for a further 18 hours. The reaction mixture was quenched with water and evaporated at reduced pressure. The residue dissolved in iso-butanol and washed with water. The organic phase was evaporated at reduced pressure and the crude material was purified by reverse phase preparative HPLC to afford the title compound (0.072 g, 16%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[N:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31]C(C)(C)C(C)(C)O3)=[C:23]([CH:36]=[O:37])[CH:22]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[N:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]3[B:27]([OH:31])[O:37][CH2:36][C:23]=3[CH:22]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(NCCOCc4ccccc4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1NCCOCc1ccccc1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a clear solution of 2-(2-benzyloxy-ethylamino)-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (7, 9 g, 18 mmol) in MeOH (anhydrous, 200 mL) was slowly added NaBH4 (4.11 g, 108 mmol). The reaction was stirred at room temperature 4 hours, before the addition of HCl solution (1 M, 200 mL). The stirring was kept at room temperature overnight. Then the solution was slowly evaporated in vacuo. The solid formed was filtered, washed with water and air-dried to give 3.3 g (45.6% yield) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]12.[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=O)=[CH:24][CH:23]=1>O=S(Cl)Cl>[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]2[O:14][C:12]([C:8]3[CH:7]=[C:6]4[C:11]([C:2](=[O:1])[N:3]5[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]5=[N:5]4)=[CH:10][CH:9]=3)=[N:29][N:28]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc2c(=O)n3c(nc2c1)CCCCCC3
Reactant: NNC(=O)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: O=c1c2ccc(-c3nnc(-c4ccc(F)cc4)o3)cc2nc2n1CCCCCC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 6.4 %

Procedure:
A solution of 13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (80 mg, 0.28 mmol) in SOCl2 (3 mL) was stirred at reflux for 0.5 h. The reaction mixture was concentrated and diluted with toluene (5 mL). 4-fluorobenzohydrazide (54.4 mg, 0.35 mmol) was added to the solution and heated to 60° C. After stirring for 1.5 h, the toluene was evaporated. Phosphoryl trichloride (3 mL) was added to the residue and heated at 80° C. for 1.5 h. Excess phosphoryl trichloride was removed under reduced pressure and diluted with water (25 mL). The mixture was adjusted to pH around 7 with aqueous Na2CO3 solution. The aqueous mixture was extracted with ethyl acetate (3×20 mL), dried over Na2SO4. After filtration, the filtrate was concentrated and purified by column chromatography to give the desired product (7 mg). MS (ESI): 391 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.43-8.39 (m, 2H), 8.23-8.16 (m, 3H), 7.29 (s, 1H), 7.24 (s, 1H), 4.38 (s, 2H), 3.11-3.07 (t, J=6.1 Hz, 2H), 2.05-1.93 (m, 4H), 1.65 (m, 2H), 1.49 (broad, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]#[N:29]>CN(C=O)C>[C:28]([CH2:27][CH2:26][CH2:25][N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)#[N:29]
Reactant: N#CCCCBr
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCCC#N)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and 4-bromobutyronitrile in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (67%), m.p. (EtOAc) 157-159° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.30 (s, 1H), 8.51 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.61 (br d, J=8.4 Hz, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.46 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.96 (t, J=7.2 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 1.93 (pentet, J=7.2 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). Anal. Calcd for C18H17FIN3O3: C, 46.1; H, 3.7; N, 9.0. Found: C, 46.4; H, 3.6; N, 8.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.C(N(CC)CC)C.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>ClCCl>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:32]
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@H](NC(=O)Cc2ccccc2Br)[C@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.8 %

Procedure:
To a solution of 250 mg (1.2 mmol) of (4S,5S)-amine 1 in dichloromethane (3 mL) was added 0.16 mL (1.2 mmol) of triethylamine followed by dropwise addition of 0.17 mL (1.2 mmol) of 2-bromophenylacetyl chloride. After stirring for ˜96 h at 25° C., the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexanes/ethyl acetate) to yield 290 mg (60%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: CCOC(=O)c1noc(Cc2cccc(C)c2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)c1
Yield: 66.7 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3-methylbenzyl)-1,2,4-oxadiazole-3-carboxylate (0.107 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.114 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[C:6]1[N:7]([CH3:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[CH:10]=1)[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:11][C:9]1[CH:10]=[C:6]([C:5](=[O:18])[C:4]([O:3][CH2:1][CH3:2])=[O:19])[N:7]([CH3:17])[C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(=O)c1cc(C)c(C(=O)OCC)n1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)c1cc(CBr)c(C(=O)OCC)n1C

Procedure:
Ethyl-1,4-dimethyl-5-ethoxycarbonyl-α-oxopyrrole-2-acetate (14.79 g, 55.5 mmol) is dissolved in carbon tetrachloride (300 ml) and placed in a 500 ml round bottom flask. Then N-bromosuccinimide (11.1 g, 62.5 mmol) is added, a reflux condenser is attached and the system is flushed with nitrogen. The mixture is slowly stirred. A 120 V, 150 W G.E. projection lamp is placed against the side of the flask and the lamp and the flask are enclosed in aluminum foil. The reaction mixture is then irradiated for one hour. The lamp is then removed, the solution is cooled and the succinimide is filtered off. The solvent is removed to give a yellow oil which solidifies. This material is then used immediately in the next reaction (vide infra).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[CH:5]2.[OH-].[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)=[CH:5]2
Reactant: COC(=O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1
Yield: 66.7 %

Procedure:
A solution of methyl 4-(5,6-dichloro-1H-indol-2-yl)benzoate (0.86 g, 2.7 mmol) and KOH (0.36 g, 6.4 mmol) in a mixture of EtOH (15 ml) and water (15 ml) was refluxed for 3 h. After concentration of the ethanol, the solution was acidified and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo to afford 0.58 g (1.8 mmol, yield 70%) of the acid used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1)#[N:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:35]([C:34]3[CH:33]=[N:32][C:31]([C:29]#[N:30])=[CH:39][CH:38]=3)=[O:36])[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(C#N)nc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(6-cyano-pyridine-3-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 6-cyanonicotinic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 543.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O)([O-])=O>C(OCC)(=O)C.C(O)C.C(Cl)Cl.[Pd]>[CH:9]1[CH:10]=[CH:11][N:7]2[CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[NH:1][CH2:12][C:8]=12
Reactant: O=Cc1cccn1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc2c(c1)Cn1cccc1CN2
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A mixture of 30.6 g of 1-(2-nitrobenzyl)-2-pyrrolecarboxaldehyde and 3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml of ethyl alcohol is hydrogenated over 18 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is treated with activated carbon and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a residue which is dissolved in methylene chloride containing ethyl alcohol. The solution is passed through a pad of silica gel and the pad washed with a 7:1 hexane-ethyl acetate solution to give 16.31 g of the desired product as solid, m.p. 145°-148° C.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[CH3:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:44](=[O:45])[CH:43]=[C:42]2[S:46][CH:47]=[CH:48][N:41]2[C:40]1=[O:49].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.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].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:44](=[O:45])[CH:43]=[C:42]4[S:46][CH:47]=[CH:48][N:41]4[C:40]2=[O:49])[C:24]=1[CH3:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2sccn2c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)cc2sccn2c1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 33.9 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (0.139 g, 0.364 mmol), 6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione [Intermediate 36] (0.127 g, 0.331 mmol) and Cs2CO3 (0.215 g, 0.661 mmol) in THF (3.0 mL) and water (0.75 mL) was bubbled with argon for 3 min, then was treated with PdCl2(dppf) DCM adduct (0.013 g, 0.017 mmol). The mixture was bubbled with argon for 30 sec more and the reaction vessel was sealed. The mixture was stirred at 50° C. for 5 h. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers was extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (90%, then 100%), to give 3-chloro-4-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a tan solid (62.7 mg, 32% yield). This material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH (60:40) at 85 mL/min; sample preparation: 9 mg/mL in MeOH-DMSO; injection: 2 mL. The third peak eluted from the column provided one single atropisomer of 3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Example 38]. Mass spectrum m/z 559 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.27 (br. s., 1H), 8.14 (s, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.69 (dd, J=4.6, 0.7 Hz, 1H), 7.59 (br. s., 1H), 7.54-7.49 (m, 1H), 7.47-7.43 (m, 1H), 7.26 (dd, J=7.4, 1.2 Hz, 1H), 7.03 (d, J=4.6 Hz, 1H), 6.99 (dd, J=8.6, 1.5 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.28 (s, 1H), 4.98 (s, 1H), 1.70 (s, 3H), 1.45-1.42 (m, 6H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10]([Cl:12])=[O:11])(=[O:6])=[O:5].C(N(CC)CC)C.[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[ClH:12].[CH2:31]([O:38][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:5])(=[O:6])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCc1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)OCc3ccccc3)cc2S(=O)(=O)N(C)C)CC1
Temperature: 25 °C

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were dissolved in 0.5 l of benzyl alcohol. 50 Milliliters of triethylamine were added dropwise to the solution, while stirring at room temperature. The mixture was then heated for 10 minutes on the steam bath and was subsequently evaporated in vacuo.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][CH2:27]O)[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.N12CCCN=C1CCCCC2>C(Cl)(Cl)Cl>[O:31]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH:26]=[CH2:27])[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:7]1
Reactant: O=C1O[C@@H](Cn2cc(CCO)nn2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: C=Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Yield: 73.9 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 51) (142 mg, 0.31 mmol) was suspended in dry chloroform (15 ml), thionylchloride (37 mg, 0.93 mmol) was added and the resulting mixture was refluxed for 12 hours. The solvent and eccess of thionylchloride was removed under vacuum and the residue was dissolved in acetonitrile (15 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (71 mg, 0.47 mmol) was added and the resulting mixture was refluxed for 12 hours. The solvent was removed under vacuum and the residure was purified by flash chromatography on silica gel with 1.5% methanol in dichloromethane to give the title product (100 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].C1(=O)N([CH:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:60])[CH2:47][CH2:48][CH2:49][CH2:50][C@H:51]2[C@@H:59]3[C@@H:54]([NH:55][C:56]([NH:58]3)=[O:57])[CH2:53][S:52]2)[C:38]([O-])=[O:39])C(=O)CC1>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:7]([NH:6][C:4]([CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:60])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH:59]3[CH:54]([NH:55][C:56](=[O:57])[NH:58]3)[CH2:53][S:52]2)=[O:5])[S:8][C:9]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[N:14]=1
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCC(C(=O)[O-])N1C(=O)CCC1=O
Reactant: Cc1nc(NC(=O)CCN)sc1-c1ccnc(Nc2ccc(N3CCOCC3)cc2)n1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCNC(=O)CCCCCNC(=O)CCCCC2SCC3NC(=O)NC32)sc1-c1ccnc(Nc2ccc(N3CCOCC3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-amino-N-{4-methyl-5-[2-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-thiazol-2-yl}-propionamide (75 mg, 0.17 mmol) in DMF (1 mL) was treated with succinimidyl-6-(biotinamido)hexanoate (32 mg, 0.085 mmol). After stirring at room temperature for 3 h, the reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound as an orange solid. Anal. RP-HPLC: tR=13.2 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). MS (ESI+) m/z 776 (C37H50N10O5S2 requires 778.9).