Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([NH:13][C:14](=[O:30])[CH2:15][NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][CH:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]2)=[CH:40][CH:39]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[S:17]([NH:16][CH2:15][C:14]([NH:13][CH:4]([C:5]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6])[CH2:3][NH:2][C:50]([CH:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][N:38]=[CH:43][CH:42]=2)[CH2:49][CH2:48]1)=[O:51])=[O:30])(=[O:19])=[O:18]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCC(NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
N-[2-Amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamide hydrochloride salt (2.6 g) and triethylamine (3.18 ml) were added in turn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 89:10:1 mixture of ethyl acetate, methanol and ammonia as eluent. The material so obtained was triturated under diethyl ether to give 2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)-piperidin-4-ylcarbonylamino]ethyl}acetamide as a foam (1.9 g, 55%);
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][OH:19]>>[CH3:18][O:19][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: OCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CO
Agent: [Na]
Product: COc1ccc(N2CCC(CCO)CC2)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
5.7 Parts of sodium (in pieces) were added to 86 parts of methanol. After the dropwise addition of 12.1 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidineethanol, the reaction mixture was stirred overnight at reflux temperature. After cooling, the whole was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of methylbenzene and methanol (90:10 by volume) as eluent. The desired fraction was collected and the eluent was evaporated, yielding 7.3 parts (61.5%) of 1-(6-methoxy-3-pyridazinyl)-4-piperidineethanol as a residue (int. 95).
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:66]([NH:68][CH3:69])=[O:67])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.Cl[C:115]1[C:120]([C:121]([F:124])([F:123])[F:122])=[CH:119][N:118]=[C:117]([NH:125][C:126]2[CH:140]=[CH:139][C:129]([CH2:130][P:131](=[O:138])([O:135][CH2:136][CH3:137])[O:132][CH2:133][CH3:134])=[CH:128][C:127]=2[CH3:141])[N:116]=1>>[OH:65][CH2:64][CH2:63][CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:66](=[O:67])[NH:68][CH3:69])[C:51]([NH:50][C:119]3[C:120]([C:121]([F:124])([F:122])[F:123])=[CH:115][N:116]=[C:117]([NH:125][C:126]4[CH:140]=[CH:139][C:129]([CH2:130][P:131](=[O:138])([O:135][CH2:136][CH3:137])[O:132][CH2:133][CH3:134])=[CH:128][C:127]=4[CH3:141])[N:118]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(C)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(C)c1)OCC
Yield: 66 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with Compound 6C and Compound 1 E with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methylbenzyl)phosphonate (Compound 33C, 339 mg, 774 μmol) to afford 345 mg of the title compound (66%). 1H NMR (400 MHz, CD3OD) δ 8.90 (br. s., 1H), 8.49 (s, 1H), 8.31 (d, J=10.1 Hz, 2H), 7.63 (d, J=9.1 Hz, 1H), 7.35-7.39 (m, 1H), 7.33 (s, 1H), 7.24-7.31 (m, 1H), 4.32 (t, J=7.0 Hz, 2H), 4.11 (quin, J=7.3 Hz, 4H), 3.56-3.61 (m, 2H), 3.33 (d, J=21.0 Hz, 2H), 3.00 (s, 3H), 2.28 (s, 3H), 2.12 (quin, J=6.5 Hz, 2H), 1.24-1.30 (m, 6H). MS (ESI): m/z=677.21 [M+H]+. UPLC: tR=1.42 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12]([O:14]C)=[O:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C(OC(N1CCC(COC(C2C3C(=CN(COCC[Si](C)(C)C)N=3)C=C(Cl)C=2)C(O)=O)(C2C=CC(F)=CC=2)CC1)=O)(C)(C)C>ClCCl.CO>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][O:16][CH:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][N:6]=[CH:5]3)[C:12]([OH:14])=[O:13])([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate using 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid as the starting material and using dichloromethane/methanol in its purification. tR=3.03 min (Phenomenex C18 3.0×50 mm, A=90% H2O/10% methanol, B=90% methanol/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 3.0 min=100% B, 5.0 min=100% B, Flow rate=4 mL/min). Mass spec.: 518.22 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[C:21](Cl)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=[O:19])[CH3:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:15]([O:17][C:18]([C:20]1[C:21]([N:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)CCNC1CCCCC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN(c1nc(SC)ncc1C(=O)OCC)C1CCCCC1
Reaction time: 16 h
Yield: 82.4 %

Procedure:
3-Cyclohexylamino-propionic acid ethyl ester (1.0 g, 5.0 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.17 g, 5.02 mmol) were combined in DCM (15 mL) and diisopropylethylamine (0.81 g, 6.3 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided 1.63 g (84%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.39 (s, 1H) 5.30 (s, 1H), 4.30 (q, 2H, J=7.1 Hz), 4.14 (q, 1H, J=7.1 Hz), 3.76-3.80 (m, 2H), 2.65-2.69 (m, 2H), 2.49 (s, 3H), 1.81-1.84 (m, 2H), 1.34-1.40 (m, 7H), 1.12-1.27 (m, 7H).
Reaction SMILES: CC(C)=O.[N-:5]=[N+:6]=[N-:7].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>O>[N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN=[N+]=[N-]
Temperature: 65 °C
Yield: 67 %

Procedure:
A mixture of 6:4 acetone:water (20 ml) to was added to sodium azide (1.30 grams, 20 mmol, 2 molequivalents) followed by addition of ethyl bromoacetate (1.67 grams, 10 mmol, 1 molequivalent). The resulting mixture was refluxed overnight at 65° C. The acetone was thereafter evaporated under reduced pressure and the mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic phase was washed with water, dried over sodium sulfate and evaporated to give 865 mg (76% yield) of ethyl azidoacetate as colorless oil having purity higher than 98% (as determined by NMR).
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]1[C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:18][S:17](=[O:25])(=[O:24])[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>CO>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[S:17](=[O:25])(=[O:24])[NH:18][C:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]=2[CH2:14][NH:5][CH2:4][CH2:3][F:2])=[CH:31][CH:30]=1
Reactant: O=S1(=O)NC2(CCCC2)C(CBr)=C1c1ccc(Cl)cc1
Reactant: NCCF
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S1(=O)NC2(CCCC2)C(CNCCF)=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-fluoroethylamine hydrochloride (1.08 g, 10.9 mmol; prepared as described in J. Med. Chem. 9 (1966), 892-911) in 30 mL of absolute MeOH was treated with triethylamine (2.50 mL, 1.76 g, 17.4 mmol) at 0° C. Solid 4-bromomethyl-3-(4-chlorophenyl)-2,2-dioxo-2-thia-1-aza-spiro[4.4]non-3-ene (1.64 g, 4.35 mmol; described during the preparation of Intermediate 6) was added. The resulting mixture was stirred for 16 h at ambient temperature and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol as eluent to yield the title intermediate. Yield: 1.00 g (64%); MS (IS): 359.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)=[O:13]
Reactant: O=Cc1cn(CCl)c2ccccc12
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(C=O)c2ccccc21
Yield: 53.8 %

Procedure:
3.02 g of 1-(chloromethyl)-3-formyl-1H-indole and 2.53 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 45 ml of N,N-dimethylformamide. 4.35 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.68 g of [{3-formyl-1H-indole-1-yl}methyl](3,3,3-trifluoropropyl)malononitrile(referred to as the compound of the present invention (40), hereinafter) shown by below formula.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:22][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
43.2 g of 2,3-diphenylbenzo[b]furan, 31.3 g of N-bromosuccinimide, and 400 mL of N,N-dimethylformamide were loaded into a flask, and the mixture was stirred under heat at 70° C. for 8 hours. After having been cooled to room temperature, the reaction solution was poured into 2 L of water. The precipitated crystal was separated by filtration, washed with methanol, water, and methanol in the stated order, and purified by silica gel column chromatography, whereby 40.2 g of a pale yellow crystal were obtained (72% yield).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18].C(N(CC)CC)C>C(#N)C>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 3-chloro-benzo[d]isothiazole 1,1-dioxide (300 mg, 1.49 mmol) and 2-amino-N-(-4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt (500 mg, 1.37 mmol) was prepared in 5.5 mL of acetonitrile. Triethylamine (575 μL, 4.10 mmol) was added and the reaction mixture was stirred at room temperature for 1 day. The suspension was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The resulting residue was chromatographed over 50 g of flash silica using dichloromethane/methanol 9:1 as the eluant to provide the desired product as a light yellow solid (310 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 0.25-0.45 (m, 1H), 0.65-0.85 (m, 2H), 0.95-1.10 (m, 2H), 1.30-1.60 (m, 7H), 1.75-1.85 (m, 2H), 1.85-2.2 (m, 2H), 2.31 (s, 3H), 2.35-2.50 (m, 3H), 2.65-2.80 (m, 2H), 4.60-4.70 (m, 1H), 7.35-7.50 (m, 2H), 7.58 (t, J=7.3, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.81 (br s, 1H), 8.91 (br s, 1H). MS, m/z 458=M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][CH2:12][C:13](O)=[O:14].C(OCC)(=O)C>FC(F)(F)S(O)(=O)=O>[Cl:10][CH2:11][CH2:12][C:13]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[CH:4][C:5]=1[OH:8])=[O:14]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(CCCl)c1cc(Cl)c(O)cc1O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chlorobenzene-1,3-diol (100 g, 692 mmol) and 3-chloropropanoic acid (75.1 g, 692 mmol) in trifluoromethanesulfonic acid (295 ml) was stirred at 75° C. for 30 minutes. The reaction was cooled to ambient temperature and slowly poured into a 2 L beaker filled with ice. To the slurry was added ethyl acetate with stirring until all solids dissolved. The mixture was poured into a separatory funnel, the aqueous layer was removed and the resulting organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatograph (silica) eluting with a solvent system mixture of 15% ethyl acetate/hexanes to provide the desired product (162.6 g, 86%).
Reaction SMILES: [Br:1][C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.Cl.O1CCOCC1>CO>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:17]1[C:2]([Br:1])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C[C@H](N)COc1cc2c(cc1Br)c1ccncc1c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 1.586 mmol) in anhydrous methanol (5 mL) was added a 4 M solution of HCl in 1,4-dioxane (2 mL, 8 mmol) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was then was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC (10 mM ammonium acetate in water; acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-bromo-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (20 mg, 0.049 mmol, 30% yield) as an off-white solid. LC/MS (ESI) m/e 404.1 [(M+H)+, calcd for C19H23BrN3O2 404.1]; LC/MS retention time (method A): tR=1.47 min; HPLC retention time (method A): tR=9.55 min; HPLC retention time (method B): tR=10.23 min; 1H NMR (400 MHz, CD3OD) δ ppm 9.48 (s, 1H), 8.80 (d, J=5.77 Hz, 1H), 8.67 (s, 1H), 8.26 (d, J=5.77 Hz, 1H), 7.15 (s, 1H), 4.37 (dd, J=9.54, 3.76 Hz, 1H), 4.18 (dd, J=9.66, 6.40 Hz, 1H), 3.83 (s, 3H), 3.48-3.56 (m, 1H), 1.89 (m, 1H), 1.51-1.72 (m, 2H), 1.05 (t, J=6.27 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.CC1(C)[O:31][CH:30]([CH2:32][NH2:33])[CH2:29][O:28]1.Cl>CO>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH:30]([OH:31])[CH2:29][OH:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC1(C)OCC(CN)O1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: Cl
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CO)c2c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.5 mL, 3.8 mmol) was heated with stirring at 160° C. for 16 hours. After being cooled to room temperature, the resulting reaction mixture was diluted with methanol (2.0 mL). Concentrated hydrochloric acid (12.0 N, 0.5 mL) was introduced to the above mixture. The resulting mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 69.2 mg of the product as a white solid (yield was 30%). MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[C:6]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[CH:5]=[C:4]([C:32]2[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:33]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.C(N(CC)CC)C.Cl[C:52](Cl)([O:54]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:13]1([NH:12][C:10]([N:9]2[CH2:8][C:7]3[C:6]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)=[CH:5][C:4]([C:32]4[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:33]=4[O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[N:3][C:2]=3[NH:1][C:52]2=[O:54])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNC(=O)NC2CCCCC2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(C(=O)NC2CCCCC2)C(=O)N3)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-{2-amino-3-({[(cyclohexylamino)-carbonyl]amino}methyl)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (0.039 g, 0.065 mmol), which was obtained in the step (1) of Example 23-3, and triethylamine (15.0 mL, 0.389 mmol) in tetrahydrofuran (10.0 mL) was added dropwise a solution of triphosgene (0.019 g, 0.065 mmol) in tetrahydrofuran (5.0 mL) under an argon atmosphere. The mixture was stirred at 0° C. for 2 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue (white solid) was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give tert-butyl 3-{3-[(cyclo-hexylamino)carbonyl]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl}-1-piperidinecarboxylate (0.021 g, yield; 52%).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[CH:39]=[N:40][C:41]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])=[N:42][CH:43]=1>>[C:3]([C:2]([CH3:36])([CH3:1])[CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[N:40][C:41]([C:44]([NH:46][CH:47]4[CH2:48][CH2:49]4)=[O:45])=[N:42][CH:43]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1ncc(Br)cn1
Product: C[C@@H](c1ccc(-c2cnc(C(=O)NC3CC3)nc2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 5-bromo-N-cyclopropylpyrimidine-2-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.237 min, m/z=524.3; 1H NMR (CDCl3) 0.62 (m, 2H), 0.83 (m, 2H), 1.32 (s, 3H), 1.44 (s, 3H), 1.49 (d, 3H), 2.08 (m, 2H), 2.24 (m, 1H), 2.42 (m, 2H), 2.90 (m, 2H), 5.61 (m, 1H), 6.93 (m, 2H), 7.20-7.36 (m, 7H), 8.00 (s, 1H), 8.88 (s, 2H).
Reaction SMILES: [O:1]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[O:1]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH:22][C:26](=[O:27])[O:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.75 h
Yield: 11.8 %

Procedure:
To a solution, at 0° C., of 0.120 g (3.51 mmol) of 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylamine in 25 ml of dichloromethane are added dropwise 1.42 g (7.03 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 5 ml of dichloromethane. 0.63 ml (3.5 mmol) of diisopropylethylamine is then added. Stirring is continued at 0° C. for 45 minutes, and the temperature of the mixture is then allowed to return to 0° C. over 1 hour. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out on a hydrophobic filter cartridge and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of silica gel, eluting with a mixture of 5 to 40% ethyl acetate in cyclohexane, to give 0.21 g of 4-nitrophenyl 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylcarbamate in the form of an oil.