Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)([CH3:6])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:6][C:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CC1(C)CCC(C)(C)c2cc(C(C)(C)C(=O)O)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.66 g of 2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoic acid dissolved in 14 ml THF were treated with 24 ml of 1M lithium aluminium hydride solution in ether. The mixture was stirred at room temperature for 18 hours. The mixture was quenched by slowly adding Na2SO4.H2O until no more H2 evolved. The solid was filtered off and the solvent was evaporated, giving a pale yellow oil which was purified by flask chromatography (SiO2, 10% ethyl acetate/hexanes). 1H NMR (CDCl3): 7.29 (d, J=2.2 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.12 (dd, J=8.3, 2.2 Hz, 1H), 3.55 (br. d, J=5.4 Hz, 2H), 1.67 (s, 4H), 1.31 (s, 6H), 1.28 (s, 6H), 1.27 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([C:14]#[N:15])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2occc2C)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccoc1-c1nc(N)nc(OCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-(3-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C.C(OCC)(=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([Br:3])=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([Br:17])[CH:13]=3)=[CH:28][CH:29]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)cc1
Temperature: 60 °C

Procedure:
In a 250 ml one-neck flask provided with a reflux condenser, 990 mg (41.2 mmol) of NaH were suspended in 80 ml of dry DMF under protective gas. 10 g (30.8 mmol) of 3,6-dibromocarbazole in 80 ml of DMF were added dropwise to this reaction mixture at RT over a period of 20 minutes. A solution of 4-(tert-butyl)-benzyl bromide in 50 ml of DMF was subsequently added dropwise and the mixture was heated at 60° C. for 8 hours. After cooling to room temperature, 300 ml of water and 200 ml of ethyl acetate were carefully added. The organic phase was washed with 4×50 ml of H2O, then dried over MgSO4 and the solvents were removed under reduced pressure. The pure product was obtained by recrystallization from n-hexane. Yield: 11 g (78%); HPLC purity: 99.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:21].Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])=[N:28][C:23]([NH:21][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:24][CH:25]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCN(C)CC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CCC(N1CCN(C)CC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-(4-methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was prepared in an analogous manner to Example 179. Product was isolated as a single diastereomer (21.7 mg, 7%). LCMS (m/e) 552 (M+H); 1H NMR (CDCl3, 400 MHz) δ 11.74 (s, 1H), 9.13 (d, 1H, J=8.08 Hz), 7.71 (s, 1H), 7.62 (d, 1H, J=8.34), 6.90 (d, 1H, J=8.34 Hz), 6.30 (m, 1H), 6.10 (m, 1H), 5.91 (s, 1H), 5.53 (s, 1H), 4.00 (t, 1H, J=7.32 Hz), 3.72 (s, 3H), 3.42-3.58 (m, 8H), 3.08 (s, 1H), 2.90 (m, 1H), 2.88 (s, 1H), 2.83 (s, 3H), 2.75 (m, 2H), 2.35-2.45 (m, 6H), 2.10 (d, 1H, J=10 Hz), 1.59 (d, 1H, J=8.33 Hz), 1.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[CH2:15]([O:17][C:18]([N:20]1[C:24]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:40]([O-:42])=[O:41])=[C:23]2[CH2:44][NH:45][C:46]([CH3:48])([CH3:47])[C:22]2=[N:21]1)=[O:19])[CH3:16].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:15]([O:17][C:18]([N:20]1[C:24]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:40]([O-:42])=[O:41])=[C:23]2[CH2:44][N:45]([S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])[C:46]([CH3:47])([CH3:48])[C:22]2=[N:21]1)=[O:19])[CH3:16]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CNC2(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Reaction time: 4 h

Procedure:
3,5-difluoro-benzenesulfonyl chloride (1 eq., 3.9 g, 18.4 mmol) was added portion-wise to a stirred solution of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (10 g, 18.4 mmol) and N,N-diisopropylethylamine (6 eq, 19.3 mL, 110.4 mmol) in dry dichloromethane (100 mL) at room temperature. Stirring was continued for about 4 hours. The reaction mixture was diluted with dichloromethane (100 mL) then washed with saturated sodium hydrogen carbonate (150 mL), dried over sodium sulphate, evaporated to dryness and purified by flesh chromatography on silica gel using acetone as the eluant. The title compound was obtained as yellow solid (9 g, 65% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](C3C(O)=CC=CN=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]3=[O:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=c1cccc[nH]1
Reactant: Oc1cccnc1C1=CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1ccccn1C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
A solution of 4-dioxaspiro[4.5]decan-8-yl methanesulfonate (497 mg, 2 mmol) from example 1, step A and pyridin-2(1H)-one (200 mg, 2 mmol) in DMF was treated with Cs2CO3 (1 g, 3 mmol) and heated at 80° C. for 18 h. DMF was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[C:10]([CH2:17]O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[C:10]([CH2:17][Cl:39])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2cccnc21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(tert-butyloxycarbonyl)-3-(hydroxymethyl)-7-azaindole (Int-17, 8.4 g, 34 mmol), triphenylphosphine (9.9 g, 37 mmol), dry CCl4 (50 mL) in dry DMF (35 mL) were stirred at room temperature for 48 h. Solvents were removed and the residue was purified by flash column chromatography to give chloride Int-14 (3.45 g, 38%).
Reaction SMILES: [C:1]1([CH:7]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:26])[CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:34]2[CH2:38][C@H:37]([NH:39][C:40](=[O:50])[C@H:41]([O:43]C3C=CC=CC=3)[CH3:42])[C@@H:36]([OH:51])[C@H:35]2[OH:52])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>CCO.C1COCC1.[OH-].[Pd+2].[OH-]>[C:1]1([CH:7]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:26])[CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:34]2[CH2:38][C@H:37]([NH:39][C:40](=[O:50])[C@H:41]([OH:43])[CH3:42])[C@@H:36]([OH:51])[C@H:35]2[OH:52])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](Oc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (R)—N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-phenoxy-propionamide (83 mg, 0.104 mmol) in EtOH (20 ml) and THF (5 ml) under an inert atmosphere is treated with palladium hydroxide (20% w/w on carbon, 32 mg) followed by acetic acid (2 ml). The reaction mixture is placed under an atmosphere of hydrogen for two weeks after which time, the mixture is filtered and concentrated in vacuo. The resulting crude product is washed with EtOH (3 times), filtered and then concentrated in vacuo. The residue is dissolved in MeOH (2 ml) and purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% NH3) affords the title compound as a white solid. (MH+ 707.4)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[CH3:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][NH2:12])=[CH:4][C:3]=1[CH3:10]
Reactant: CN
Reactant: Cc1cc(C=O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C=CN)ccc1Br
Reaction time: 72 h
Yield: 80 %

Procedure:
4-Bromo-3-methylbenzaldehyde (D80, 3.7 g, 18.6 mmol) was treated with methylamine in ethanol (33%, 100 ml) followed by 4 Å molecular sieves and solid potassium carbonate (approx 4 g) and the mixture stirred for 72 hours. Solvent was removed in vacuo, the residue suspended in chloroform, and the solid removed by filtration. The filtrate was evaporated in vacuo to yield the title compound as a red liquid (3.15 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](=[O:21])(=[O:20])[NH2:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:27])([CH3:26])[C:24]#[CH:25]>>[CH3:22][C:23]([CH3:27])([CH3:26])[C:24]#[C:25][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](=[O:21])(=[O:20])[NH2:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)C
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(C)C#Cc1cccc(S(=O)(=O)Nc2ccccc2S(N)(=O)=O)c1
Yield: 27 %

Procedure:
The title compound was synthesized as described for Example 179a) in 27% yield, starting from 3-bromo-N-(2-sulfamoylphenyl)benzenesulfonamide and 3,3-dimethyl-1-butyne.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH:7]=[CH2:8].C[O:19][C:20]([C@:22]1([CH:39]([CH3:41])[CH3:40])[CH2:26][C:25]2[CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:30][C:24]=2[O:23]1)=[O:21]>>[Cl:1][C:2]1[CH:12]=[C:11]([O:13][C:14]([F:16])([F:15])[F:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:28]1[CH:29]=[CH:30][C:24]2[O:23][C@:22]([CH:39]([CH3:40])[CH3:41])([C:20]([OH:21])=[O:19])[CH2:26][C:25]=2[CH:27]=1
Reactant: C=CCCOc1ccc(OC(F)(F)F)cc1Cl
Reactant: COC(=O)[C@]1(C(C)C)Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2O1
Product: CC(C)[C@@]1(C(=O)O)Cc2cc(CCCCOc3ccc(OC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the procedure described in Example 16, Step 3, employing the intermediate prepared in Step 1 instead of 5-[(buten-3-yl)oxy]-2-ethyl2,3-dihydro-1-benzofurancarboxylate and the triflate prepared in Step 2 instead of 2-chloro-4(trifluoromethoxy)phenyl trifluoromethanesulfonate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][O:13][CH2:14][CH2:15]O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[ClH:19].[Cl:19][CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2
Reactant: O=S(Cl)Cl
Reactant: OCCOCCc1ccc2nccnc2c1
Solvent: c1ccccc1
Product: Cl
Product: ClCCOCCc1ccc2nccnc2c1

Procedure:
In 10 mL of benzene is dissolved 0.73 g of 2-[2-(6-quinoxalinyl)ethoxy]-1-ethanol, to which is added 0.32 mL of thionyl chloride. The mixture is heated under reflux for 30 minutes. The solvent is distilled off and the deposited crystal is collected by filtration to obtain 0.37 g of 6-[2-(2-chloroethoxy)-ethyl]-quinoxaline hydrochloride.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O.Cl>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][C:22](=[O:24])[N:32]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CCC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-[3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in DCM (0.01 M), 3.5 eq of DIPEA and 1.5 eq of HATU were added and the mixture was stirred at RT for 4 h. The solution was diluted with EtOAc and HCl (1 N), the aqueous phase was re-extracted with EtOAc (twice) and the combined organics then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was used in the next step without further purification; MS (ES+) m/z 488 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Li])CCC.[CH3:15][N:16]([CH3:30])[C:17]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:18]=1C(Cl)=O.C(O[Li])(=O)CC(O[Li])=O.Cl>C1COCC1.O>[CH3:15][N:16]([CH3:30])[C:17]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:18]=1[C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)CC(=O)O
Reactant: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Agent: [Li]OC(=O)CC(=O)O[Li]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1N(C)C
Temperature: -78 °C
Reaction time: 1.75 h

Procedure:
To a solution of 4.76 g (36 mmol) of malonic acid monoethyl ester and 75 ml of THF at -35° C. was added 25 ml (40 mmol) of 1.5N n-butyl lithium solution. The remaining 25 ml (40 mmol) of 1.5N butyllithium solution was added at 0° . After cooling to -78° C., a solution of the 4.8 g of 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoyl chloride in 50 ml of THF was added to the dilithio malonate over a 15 minute period. The reaction mixture was stirred for 1.75 hours while the temperature came up to -30° C. The reaction mixture was poured into ice, water, and 50 ml of 1N HCl. The mixture was extracted with ether and the ether extract was washed with H2O, 5% NaHCO3, and HCl. After drying over MgSO4 the ether solution was concentrated to 4.4 g of oil product. NMR spectra indicated the desired product.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1=CNCCN1C(=O)C(F)(F)F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1=CCCC=CCC1
Product: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)C(F)(F)F
Reaction time: 18 h
Yield: 99.3 %

Procedure:
250 g (8.95 mmol) of 1-trifluoroacetyl-1,4,5,6-tetra-hydropyrazine-2-carboxylic acid tert-butylamide, 7.5 mg (18 μmol) of bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate and 11.5 mg (21 μmol) of 1-[1(R)-(di-tert-butylphosphino)ethyl]-2(S)-(diphenylphosphino)ferrocene were placed in a 50 ml autoclave under argon (educt:catalyst=486). 20 ml of degassed ethyl acetate was added and hydrogenation was carried out for 18 hours at 90° C. under a hydrogen pressure of 13-10 bar. After distillation of the solvent, 2.50 g of the crude title compound was obtained in the form of a light yellow powder. After cleavage of the protecting groups, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 47.2 percent. Other data concerning the title compound was:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[C:25]4[S:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:15]=2[OH:33])=[CH:3][CH:2]=1.C(Cl)Cl.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>O>[C:44]([O:33][C:15]1[CH:16]=[CH:17][C:18]([C:20]2[C:25]3[S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:19][C:14]=1[C:4]1[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)(=[O:47])[CH:45]=[CH2:46]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Reaction time: 0.5 h
Yield: 88 %

Procedure:
1.02 g of the thus obtained 2,4-bis(4-dibenzothiophenyl)phenol is placed in a round bottom flask; 5 mL of methylene chloride is added to form a transparent solution; after ice cooling the flask, 0.27 g of triethylamine is added; 0.24 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and then gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=80/20 (volume ratio)) to concentrate a component having an Rf of 0.42, thereby obtaining 1.0 g (yield: 88%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 6.05 (dd=1.2 & 10.4 Hz, 1H), 6.37 (dd=10.4 & 17.2 Hz, 1H), 6.66 (dd=1.2 & 17.2 Hz, 1H), 7.30 to 8.25 (m, 17H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)=[CH:4][CH:3]=1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:18][C:17](=[O:19])[N:16]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)o2)cc1

Procedure:
2.03 g of the compound prepared in step B, 2.5 g of trityl chloride, 50 ml of DCM and 1.6 ml of triethylamine are placed in a round-bottomed flask and the mixture is refluxed for 1 and a half hours. It is evaporated, the residue is taken up with an ethyl ether/water mixture and the organic phase is washed with a 3% solution of potassium hydrogensulfate, dried over sodium sulfate, filtered and evaporated. The product is used in the crude form for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:34])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(Cc2ccncc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(pyridin-4-ylmethyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.0202 g, 0.0530 mmol) and ammonium acetate (0.0409 g, 0.530 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.13 mL, 0.13 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H25ClN6 (M+H)+: m/z=382.2; Found: 382.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][OH:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][O:15][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a stirred solution of ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (3.0 g, 13.0 mmol, 1.0 equiv.) in dry pyridine (14.8 mL) was added tosyl chloride (3.7 g, 19.4 mmol, 1.5 equiv) portionwise at 0° C. under nitrogen. After 4 hours of stirring at room temperature, the reaction mixture was extracted with ethyl acetate (200 mL), washed with water (3×200 mL) followed by brine (2×100 mL), and dried over anhydrous sodium sulfate to give a crude residue. The residue was purified by silica gel column chromatography (100-200 mesh) using a gradient of 5-10% ethyl acetate/hexanes to give toluene-4-sulfonic acid(S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentyl ester (3 g, 60%).