Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15]2=[O:38])[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C(O[K])(C)(C)C.C([O:58][C:59]([C:61]1[N:62]2[CH:65]([S:66][CH2:67][C:68]=1[CH:69]=O)[CH:64]([NH:71][C:72](=[O:101])[C:73]([C:95]1[N:99]=[C:98]([NH2:100])[S:97][N:96]=1)=[N:74][O:75][C:76]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:63]2=[O:102])=[O:60])(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1.C1COCC1>[NH2:100][C:98]1[S:97][N:96]=[C:95](/[C:73](=[N:74]/[O:75][C:76]([C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)/[C:72]([NH:71][C@@H:64]2[C:63](=[O:102])[N:62]3[C@@H:65]2[S:66][CH2:67][C:68](/[CH:69]=[C:16]2/[C:15](=[O:38])[N:14]([C@@H:11]4[CH2:12][CH2:13][N:9]([C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])[CH2:10]4)[CH2:18][CH2:17]/2)=[C:61]3[C:59]([OH:60])=[O:58])=[O:101])[N:99]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC([P+](c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)C1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=O)CSC23)ns1
Agent: CC(C)(C)O[K]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
4.2 (small scale): To a solution of 2.45 g of (1′-tert.-butoxycarbonyl-2-oxo-[1,3′]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium bromide (preparation according EP 1 067 131 A1) in 6 ml of dichloromethane and 15 ml of toluene was added at −78° C. a solution of 432 mg of t-C4H9OK in 6 ml of THF over 10 min and stirring was continued at −78° C. for 10 min. The solution was treated at −78° C. with a solution of 3.50 g 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester in 6 ml of THF over 15 min and stirring was continued at −78° C. for 6 h and at −50° C. for 1 h after which time HPLC showed almost completion of the reaction. The reaction was quenched with a solution of 0.95 g of citric acid in 9 ml of water followed by addition of 12 ml of ethyl acetate, the organic layer was washed with NaHCO3 and brine, dried over MgSO4, filtered and the filtrate was evaporated. The residue was chromatographed on silica with ethyl acetate/hexane 10:1 to give 1.82 g of the title compound as a foam. IR (Nujol): 3450 m (NH2, NH), 1779 s, 1724 s, 1678 s, 1653 s (C═O). 1H-NMR (d6-DMSO): 9.93 (d, J=8.8, 1H, NH); 8.13 (s, br., 2H, NH2); 7.6-7.3 (m, 26H, H—ar., HC—C(3)); 6.96 (s, 1H, CH(Ph)2); 6.15 (dd, J=8.8 and 4.8, 1H, H—C(7)); 5.33 (d, J=4.8, 1H, H—C(6)); 4.59 (m, 1H, CH—N)); 3.91, 3.85 (d each, J=18 each, 2H, CH2—S(5)); 3,5-3,3 and 2.9 and 2.7 and 2.0 (m each, 6H and 1H and 1H and 2H, 5×CH2); 1.41 (s, 9H, (CH3)3C). MS (CI): 1044/100 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tert-Butyl 3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate (from Step 5) was dissolved in DMF (0.18 M). NaH (60% suspension in mineral oil, 1.5 eq.) was added and the resultant mixture stirred for 5 min at RT, then for another 5 min at 50° C. The solution was allowed to reach RT, and then neat 2-chloro-N,N-dimethylacetamide (1.6 eq.) was added dropwise. After 1 h analytical RP HPLC indicated complete conversion of the starting material. The mixture was diluted with EtOAc, and then washed with water (3×) and brine. Drying over Na2SO4 and evaporation gave a colorless solid, which was purified by flash chromatography on silica gel using PE/EtOAc (3:1, then 2:1) as the eluent. The resulting colorless solid was immediately dissolved in a mixture of DCM and TFA (0.05 M, 1:1, v/v). After stirring for 30 min at RT, the solvents were removed in vacuo to give after drying under high-vacuum, the title compound as a light yellow foam. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.12-1.31 (m, 3H), 1.60-1.75 (m, 5H), 1.80-1.92 (m, 2H), 2.53-2.59 (m, 1H), 2.80 (s, 3H), 2.89 (s, 3H), 4.84 (s, 2H), 7.31 (d, J 6.4, 2H), 7.48-7.53 (m, 3H), 7.64 (d, J 8.4, 1H), 7.81 (d, J 8.4, 1H), 7.92 (s, 1H,); MS (ES+) m/z 405 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(#N)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OCc2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (23.8 g, 100 mmol, prepared as described in WO99/62872) in acetonitrile (200 mL) was added anhydrous potassium carbonate (31.9 g, 231 mmol) followed by benzyl bromoacetate (17.4 mL, 110 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature, insoluble salts were filtered off and the solution was concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), and the organic phase was washed with aqueous NaHCO3 (3×100 mL) and brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification on silica gel with methylene chloride as the eluent and collection of pure fractions yielded 22.4 g (58%) of a yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:17]1[CH:21]=[C:20]([CH:22]=O)[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]1=2.[BH4-].[Na+]>C(O)C>[S:17]1[CH:21]=[C:20]([CH2:22][NH:16][S:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)(=[O:15])=[O:14])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]1=2
Reactant: NS(=O)(=O)N1CCC(c2ccccc2)CC1
Reactant: O=Cc1csc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(NCc1csc2ccccc12)N1CCC(c2ccccc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-Phenyl-piperidine-1-sulfonic acid amide (1.5 g, 6.24 mmol) was dissolved in ethanol (20 mL). Benzo[b]thiophene-3-carbaldehyde (1.0 g, 6.24 mmol) was then added and the reaction mixture was warmed to 45° C. overnight. The reaction mixture was cooled to room temperature and then treated with sodium borohydride (0.2 g, 5.29 mmol). The reaction was then quenched by addition of 1N HCl. The reaction mixture was stirred overnight. The product precipitated from solution and was removed by vacuum filtration to yield the title compound as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:59]C1C=C(C=CC=1)C(Cl)=O>>[Cl:59][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Cl)c4)cc3)cc2C1=O

Procedure:
The compound of example 107 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-chlorobenzoyl chloride. The compound of example 107 was used directly without isolation for the preparation of compound of example 108.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][CH2:16][CH2:17][CH2:18]N=C=O>O1CCCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:18][CH2:17][CH2:16][Cl:15])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C=NCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCCCl)CC1
Yield: 97.5 %

Procedure:
A solution of 4-amino-1-t-butoxycarbonylpiperidine (200 mg, 1.0 mmol) in tetrahydrofuran (5 mL) was treated with 3-chloropropyl isocyanate (0.080 mL, 1.0 mmol) overnight. The solvent was evaporated to provide the title compound as a white solid (270 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:21]#[C:20][C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[N:17][C:18]=2[CH3:29])=[CH:27][CH:26]=1
Reactant: Cc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: Cl
Product: Cc1ncnc(N2CCNCC2)c1C#Cc1ccc(N)nc1

Procedure:
A solution of 7.5 g (19.1 mmol) 4-[5-(6-Amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester in 50 mL 4 M HCl (in dioxane) ist to stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is taken up in 50 ml DCM and washed with saturated aqueous NaHCO3 solution. After phase separation the organic solvent is removed under reduced pressure. The residue is taken up in methanol dried over Na2SO4. After 15 hours the suspension is filtered off, the residue is washed with methanol and the solvent is removed under reduced pressure. After drying 5.6 g (100%) of crude product are obtained, which are used without further purification in the next step.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[CH2:1]([C:11]1([OH:10])[CH2:12][CH2:13][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of benzylmagnesium chloride (1.90 mL of a 2M solution in THF, 3.80 mmol) at −78° C. was treated with 4-(4-oxo-1-piperidinyl)benzonitrile (prepared according to the procedure described in Synthesis 1981, 606-608, 0.30 g, 1.51 mmol), and was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to give the desired product (0.087 g, 20%). MS (ESI) m/e 293 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[Si:14]([O:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[CH:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[C:33]1=O)[CH2:39]2>C1COCC1.CCOCC>[Si:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:25][O:27][CH:28]=[C:33]2[CH:34]3[CH2:40][CH:38]4[CH2:37][CH:36]([CH2:41][CH:32]2[CH2:39]4)[CH2:35]3)[CH:29]=[CH:30][CH:31]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(COC=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A 500 mL three-neck flask was fitted with a reflux condenser, 125 mL addition funnel, and nitrogen line. The apparatus was dried by means of a hot air gun and nitrogen purging. Dry THF (200 mL) was added and the flask cooled in an ice bath. TiCL3 (24 g, 156 mmol) was added rapidly followed by LAH (2.8 g, 75 mmol) in portions with stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (12 mL, 86 mmol) was added to the stirred suspension and refluxed for 1 hour. After this period a solution of methyl 3-tert-butyldimethylsilyloxybenzoate (4.40 g, 16.6 mmol) and 2-adamantanone (3.0 g, 20.4 mmol) in 50 mL of dry THF was added dropwise to the refluxing mixture over 5 hours. Refluxing was continued for an additional 4 hours after which the reaction was cooled to room temperature and diluted with 100 mL of ether. The organic solution was separated and concentrated. Chromatography over silica with 1% ethyl acetate/hexane gave 1.29 g (21%) of 7b as an oil: 1H NMR (CDCl3) delta 0.196 (s, 6H), 0.985 (s, 9H), 1.78-1.97 (m, 12H), 2.628 (s, 1H, 3.23 (s, 1H), 3.29 (s, 3H), 6.75-7.20 (m, 4H); 13C NMR (CDCl3) delta -4.50, 18.19, 25.67, 28.37, 30.16, 32.28, 37.25, 38.19, 39.01, 57.51, 119.29, 121.08, 122.32, 128.87, 131.11, 136.84, 143.47, 155.37. ##STR45## Preparation of 1,2-Dioxetanes
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
2-Carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.86 g) and sodium carbonate (0.62 g) were dissolved in water (30 ml) using gentle warming. A solution of 2-bromoacetophenone (2.33 g) in ethanol (60 ml) was then added and the mixture boiled for 2 h. the mixture was cooled to room temperature and stood for 16 h. The mixture was again boiled for 2 h. solvent removed at reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 1:1 ethyl acetate:pentane) to give the title compound (3.14 g).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc(C2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 3.04 ml, 12.15 mmol) was added to a stirred suspension of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrimidine-5-carboxylate (976 mg, 3.04 mmol) in methanol (15.20 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(piperidin-4-yl)pyrimidine-5-carboxylate (600 mg, 89%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].[CH3:11]O>CCC(CCCCC(NC(C(NC(C(NC(C(NC1C(=O)NC(CCN)C(=O)NC(CC2C=CC=CC=2)C(=O)NC(CC(C)C)C(=O)NC(CCN)C(=O)NC(CCN)C(=O)NC(C(O)C)C(=O)NCC1)=O)CCN)=O)C(O)C)=O)CCN)=O)C.OS(O)(=O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([O:9][CH3:11])=[O:8]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CO
Agent: CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(Cc2ccccc2)NC(=O)C(CCN)NC1=O)C(C)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(=O)c1cccs1

Procedure:
To a stirred solution of 2-thiopheneglyoxylic acid (1 g) in methanol (10 ml) was added 5 drops of concentrated sufuric acid and the mixture was refluxed for 4 hours. Then the methanol was evaporated off and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried (sodium sulfate) and evaporated to give methyl 2-thiopheneglyoxylate as an oil (1.01 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH2:13]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH2:13][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)CBr
Reactant: C1CCNCC1
Solvent: CCOCC
Product: CC(=Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1

Procedure:
35 g of 3-(p-tert.butyl-phenyl)-2-methyl-allyl bromide in 70 ml of ether are added dropwise to a solution of 24.5 g of piperidine in 100 ml of absolute ether and the mixture is heated at reflux for 16 hours. The piperidine hydrobromide is removed by filtration and rinsed with ether. The ether solution is extracted with 2-N hydrochloric acid and made alkaline with 50% sodium hydroxide. The alkaline-aqueous solution is again extracted with ether, washed with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-2-propenyl]-piperidine of boiling point 96°-98° C./0.03 Torr.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Cl[C:18]1[CH:27]=[CH:26][N:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[N:23]2>>[CH2:28]([C:22]1[N:23]=[C:24]2[C:19]([C:18]([NH:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[S:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:21]=1)[CH3:29]
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 4c (131 mg, 0.530 mmol) was reacted with the product from Example 3f (97 mg, 0.503 mmol) for 21 h following the procedure from Example 1g giving the title compound as a hydrochloride salt which was triturated with 5:1 ether/THF giving (210 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.35 Hz, 3H) 2.33 (s, 3H) 3.05 (q, J=7.35 Hz, 2H) 6.29 (d, J=6.99 Hz, 1H) 6.74 (d, J=8.46 Hz, 2H) 7.00 (m, 1H) 7.17-7.29 (m, 4H) 7.84 (d, J=8.83 Hz, 1H) 8.43 (d, J=6.98 Hz, 1H) 9.09 (d, J=8.83 Hz, 1H) 9.90 (s, 1H) 11.12 (br s, 1H) 14.38 (br s, 1H); MS (ESI+) m/z 388 (M−Cl)+; (ESI−) m/z 386 (M−HCl)−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:23])[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH2:22].C(N(CC)CC)C>>[CH3:14][N:15]([CH3:23])[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C1CCCCC1N
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The titled amide was prepared according to general procedure B using p-trifluoromethyl-benzoyl chloride (4.17 g.; 0.02 mole), N,N-dimethylcyclohexane-1,2-diamine (2.84 g.; 0.02 mole) and triethylamine (2.02 g., 0.02 mole). The crude solid was crystallized from ether to give 4.766 g. (77% yield) of colorless needles, m.p. 141°-142°, raised to 141.5°-142.5° on recrystallization. uv λmax 222 nm (ε 11,450), sh 245 (5,550); sh 260 (3,400); sh 276 (1.750). ir NH 3310; =CH 3030; N-alkyl 2770, 2740; C=O 1635; C=O 1575, 1510; amide II 1550; CF3 /ether 1330, 1190, 1165, 1130, 1105, 1065, 1020; aromatic 860; nmr in CDCl3 at 100 MHz was in accord. Mass spectrum M+ 314.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:26][C:27]1[C:32]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])(=[O:36])=[O:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:31][C:32]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])(=[O:36])=[O:35]
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
A mixture of tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (Intermediate 24) (0.050 g, 0.137 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.065 g, 0.151 mmol), PdCl2(dppf)-CH2Cl2Adduct (5.61 mg, 6.87 μmol) and 1 N aq. sodium bicarbonate (0.275 ml, 0.275 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by prep TLC (Hex:EtOAc=1:2) to give tert-butyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (3.90 mg, 4.5%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.48 (9H, s), 1.55-1.72 (2H, m), 2.05-2.22 (2H, m), 2.92-3.12 (2H, m), 4.02-4.25 (2H, m), 4.30-4.48 (1H, m), 6.90-7.04 (2H, m), 7.14 (1H, J=8.0 Hz), 7.80-7.92 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz), 8.69 (1H, s), 8.70 (1H, br s), 8.79 (1H, br s). m/z=632.2 [M+1]+.