Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(C(F)(F)F)=O>>[CH3:26][C:24]1[CH:23]=[CH:22][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:25]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:21]=1)=[CH:7]3
Reactant: C1CCNC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CN4CCCC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(pyrrolidin-1-ylmethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzaldehyde (from Example 172/Step 1) and pyrrolidine following the procedures described for Example 172, step 2. 1H NMR (Acetone-d6) TFA Salt: δ 8.88 (s, 1H), 8.82 (s, 1H), 8.82 (s, 1H), 8.43 (d, 1H), 8.38 (d, 1H), 7.58 (s, 1H), 7.51 (m, 1H), 7.33 (d, 2H), 4.16 (s, 2H), 3.32-3.38 (m, 4H), 2.55 (s, 3H), 2.20-2.32 (m, 4H), 1.90-1.99 (m, 4H). LRMS [M+H]=397.2
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][C:24]=1[CH:25]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][C:24]=1/[CH:25]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.9 %

Procedure:
A solution 4-acetyl-N-pyridin-2-ylmethyl-benzenesulfonamide (Ex-53A, 617 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (20 mL) and extracted ethyl acetate (3×50 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Crystallization from hot ethanol (25 mL) and water (50 mL) gave the title compound as a red solid (626 mg, 58%), mp 112–116° C. 1H-NMR (300 MHz, DMSO-d6) 8.40 (m, 3H), 8.19 (d, 2H, J=9.0 Hz), 8.05 (d, 1H, J=15.9 Hz), 7.89 (d, 2H, J=9.0 Hz), 7.62 (m, 2H), 7.25 (dd, 1H, J=4.5, 5.7 Hz), 7.17 (s, 1H), 6.67 (s, 1H), 4.05 (d, 2H, J=5.7 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C27H29N3O5S: 508.1906 [(M+H)+]; Found: 508.1902.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12]CC>>[C:6]1([CH2:9][P:11](=[O:12])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:3]([CH2:2][P:11](=[O:12])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:4][CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1ccc(CCl)cc1
Product: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)cc1)OCC
Temperature: 180 °C

Procedure:
A mixture of α,α′-dichloro-p-xylene (20 g, 0.114 mol) and triethyl phosphite (60 ml) was refluxed at 180° C. overnight. 80 ml of hexanes was added, and white crystals were formed immediately. Then the mixture was cooled at 0° C., and the product was collected, washed three times with 40 ml of hexanes and isolated in 94.4% (40.8 g) yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[C:27]([OH:32])(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[C:27]([O:32][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)O
Reactant: CN1CCC(=NO)CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(C)C(=O)OC1(N=O)CCN(C)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl isobutyrate was prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and isobutyric acid using conditions of General Method 3. 1H NMR (400 MHz, chloroform-d) δ 2.82-2.94 (2H, m), 2.65 (1H, sept, 7.0 Hz), 2.36 (3H, s), 2.23-2.35 (4H, m), 1.83-1.92 (2H, m), 1.28 (3H, s), 1.27 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[OH:22][C:23]1C=CC(C#N)=C(OC)C=1.CC1(C)O[C@H](CO)CO1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: COc1cc(O)ccc1C#N
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Agent: CC1(C)OC[C@@H](CO)O1
Product: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (2.46 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methoxy-benzonitrile and L-α,β-isopropylidene glycerol. LC-MS: tR=0.62 min, [M+H]+=296.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[Br:25][C:26]1[CH:27]=[C:28]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:25][C:26]1[CH:27]=[C:28]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][N:8]1[C:9]2[S:15][C:14]([CH2:16][CH3:17])=[CH:13][C:10]=2[C:11](=[O:12])[N:6]([CH2:5][C:4]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=2[O:2][CH3:1])[C:7]1=[O:18]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3Br)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.4 g), 3′-bromo-4′-(bromomethyl)biphenyl-2-carbonitrile (3.8 g), potassium carbonate (2.7 g) and acetonitrile (200 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (4.92 g, 81%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][CH:27]=2)[CH:7]=1)=[O:5])C.C(OC(C1[N:41]2C=C(NC(NC(C)C)=O)N=[C:40]2[CH:39]=C(C2C=NC(N(C)C)=NC=2)C=1)=O)C.N1C=CN=C1>C(N)C.O>[CH2:40]([NH:41][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH:19]([CH3:20])[CH3:21])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:29])[CH3:30])=[N:26][CH:27]=2)[CH:7]=1)=[O:5])[CH3:39]
Reactant: CCOC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(NC(=O)NC(C)C)nn12
Reactant: CCOC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(NC(=O)NC(C)C)cn12
Agent: CCN
Agent: c1c[nH]cn1
Solvent: O
Product: CCNC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(NC(=O)NC(C)C)nn12
Temperature: 100 °C

Procedure:
A suspension of the product of Example 116, 7-(2-dimethylamino-pyrimidin-5-yl)-2-(3-isopropyl-ureido)-imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (0.149 g, 0.361 mmol) in ethylamine (2 mL of a 70% aqueous solution) was treated with imidazole (2 g) and heated to 100° C. for 1 min until it became a homogeneous solution. The reaction was cooled to 23° C. and diluted with water (15 mL). The precipitated solid was collected by vacuum filtration then dried in vacuo to give 7-(2-dimethylamino-pyrimidin-5-yl)-2-(3-isopropyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethylamide. MS (APCI+)=412.2
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[C:4]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH2:18](I)[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Br:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:7](=[O:14])[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[S:5][CH:6]=1
Reactant: O=C(c1ccncc1)c1scc(Br)c1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1c(Br)csc1C(=O)c1ccncc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of 4-bromo-2-isonicotinoylthiophene-3-carboxylic acid (311 mg, 1 mmol), ethyl iodide (234 mg, 1.5 mmol), Cs2CO3 (652 mg, 2 mmol) in CH3CN (50 mL) was stirred at 30° C. overnight. After completion of the reaction the solution was filtered and the volatile components removed under reduced pressure to give the title compound (305 mg, 90% yield) as yellow oil. The product was directly used for the next step without further purification. LC-MS (Method A): m/z 340 (M+H)+, Rt: 1.95 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:36])=[O:35]
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2Cl)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-chlorobenzenesulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2-chlorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (5.8 mg). MS m/z 407 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:18])([CH3:17])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)c1ccc(CNC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NCc1ccc(C(C)(C)C(=O)O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of methyl 2-(4-acetylaminomethylphenyl)-2-methylpropionate (23.47 g) in ethanol (160 ml) was added a solution of sodium hydroxide (7.53 g) in water (94 ml) and the mixture was stirred at 70° C. for 1 hr. The solvent was evaporated, and conc. hydrochloric acid was added. The resulting crystals were collected by filtration to give the title compound (14.0 g) as pale-yellow crystals, m.p.=166-169° C.
Reaction SMILES: C(OC([N:11]([C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.CCOCC.[BrH:28]>C(O)(=O)C>[BrH:28].[NH2:20][C@H:19]([C:18]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:22])[CH3:21]
Reactant: C[C@H](N)C(=O)N(C(=O)OCc1ccccc1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
6 g (0.02 mol) of N-benzyloxycarbonyl-L-alanine anilide were dissolved in 30 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred for 1 hour at room temperature. 300 ml of dry ether were then added. An oil precipitated out and was allowed to settle. The solvents were decanted off and the oil was washed with two 150 ml portions of ether, dissolved in a small amount of methanol and an excess of ethyl acetate was added. The product crystallised out, there being obtained 4.0 g (81%) of L-alanine anilide hydrobromide of melting point 244°-247° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1)=[O:19])C>>[Cl:30][C:25]1[CH:24]=[C:23]([CH:21]2[CH2:22][CH:20]2[C:18]([OH:19])=[O:17])[CH:28]=[CH:27][C:26]=1[O:29][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCCC2)c(Cl)c1
Yield: 70 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (49 mg, 0.23 mmol) obtained in Step C of Preparation Example 8 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (62 mg, 0.25 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (65 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([N:5]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[O:4].[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]([F:28])([F:27])[C:3]([N:5]([CH2:20][P:21]([O:25][NH:35][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([O:23][NH:35][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:22])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[O:4]
Reactant: NC1CCCCC1
Reactant: CCCCCCCCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCCCCCCCCCOC(=O)CN(CP(=O)(ONC1CCCCC1)ONC1CCCCC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of decyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.63 g, 0.015 mole) in 200 ml. of ether was added with good stirring cyclohexylamine (5.95 g, 0.06 mole) in 50 ml. of ether. The reaction was stirred overnight at room temperature, then filtered, and the filtrate concentrated in vacuo. The residue was dissolved in fresh ether, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was eluted through a dry column chromatograph with ethyl acetate to yield decyl N-trifluoroacetyl-N-(bis(cyclohexylamino)phosphonomethyl)glycinate, m.p. 79.5°-82.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.034 g, 0.085 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.085 mmol) were placed in a THF-DCM solution (1:1, 3 ml) at 0° C. The resulting suspension was shaken vigorously at 0° C. for 45 min. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.018 g, 48%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.36 (m, 2H), 7.12 (d, J=9.6 Hz, 1H), 7.04-6.99 (m, 2H), 6.09 (br s, 1H), 5.19-5.02 (m, 1H), 4.36-4.17 (m, 2H), 3.83-3.71 (m, 2H), 1.99 (s, 3H), 1.88-1.83 (m, 1H), 0.98-0.87 (m, 2H), 0.72-0.66 (m, 2H). MS: Calcd.: 442. Found: [M+H]+ 443.
Reaction SMILES: Br[CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4].[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>C(O)(=O)C>[C:23]([O:26][CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4])(=[O:25])[CH3:24]
Reactant: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(OC(C)=O)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Temperature: 6 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (323 mg) in acetic acid (3 ml) was added potassium acetate (345 mg) and the mixture was stirred at 6° C. for 2 hours. The resulting mixture was evaporated in vacuo, then he residue was diluted with ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-acetoxypropyl)-3-isobutyrylindole-6-carboxylate (207 mg).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][C:6]([NH2:11])([CH3:10])[CH2:5]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([S:27][CH3:28])[C:15]=1[C:16](Cl)=[O:17]>>[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][C:6]([NH:11][C:16](=[O:17])[C:15]2[C:19]([S:27][CH3:28])=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:14]=2[O:13][CH3:12])([CH3:10])[CH2:5]1
Reactant: CN1CCCC(C)(N)C1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Agent: Cl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(C)CCCN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-1,3-dimethyl-piperidin-3-ylamine dihydrochloride (Example A.13) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6). MS (m/e): 377.3 (MH+).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7](=[O:10])(O)[O-:8].[Na+]>C(Cl)Cl.CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:8][CH:7]1[CH2:5][CH2:4][CH2:3][CH2:2][O:10]1
Reactant: C1=COCCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C1CCC(OC2CCCCO2)OC1

Procedure:
A solution of 1.15 g of the ketone, 1.2 ml of dihydropyran and 10 mg of p-toluolsulfonic acid in 40 ml of methylene chloride is stirred for 30 minutes at 0° C. The product is then diluted with ether, shaken with dilute sodium bicarbonate solution, washed with neutral water, dried via magnesium sulfate and concentrated by evaporation in a vacuum. 1.65 g of the bis-tetrahydropyranyl ether is obtained, which is used without any further purification.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.CCN(CC)CC.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[CH2:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:2]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in US Pat. Pub. No. 2012/0101280](50 g, 160 mmol) in CH2Cl2 (500 mL), and Et3N (51.7 g, 512 mmol) was cooled to 0° C. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with water, extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo to provide (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate as a light yellow oil which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([OH:18])[CH2:20]1
Reactant: O[C@@H]1CCCNC1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCC[C@@H](O)C2)c1S(C)(=O)=O
Yield: 59.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), (R)-(+)-3-hydroxypiperidine (119 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, the residue was extracted with dichloromethane and 10% Na2CO3, and then purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 209 mg (60%) of white crystals. MS: m/z=447 (M+H).