Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[N:10]1C(=O)C2=CC=CC=C2C1=O)[C:2]#[N:3].O.NN.[ClH:24]>O1CCOCC1>[ClH:24].[S:1]([CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])[C:2]#[N:3]
Reactant: N#CSC[C@H]1NC(=O)[C@H]1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: C1COCCO1
Product: N#CSC[C@H]1NC(=O)[C@H]1N
Temperature: 20 °C
Reaction time: 0.83 h

Procedure:
A hot mixture of 1.45 g of the product of Step B in 15 ml of hot dioxane was cooled and 0.3 ml of hydrazine hydrate was added thereto. The mixture was stirred for 50 minutes at 20° C. and 7.5 ml of N hydrochloric acid were added thereto. The mixture was stirred for 15 hours and vacuum filtered. The filtrate was rinsed with water and the filtrate was evaporated to dryness to obtain 0.914 g of cis 4-thiocyanatomethyl-3-amino-2-oxo-azetidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C([Sn](CCCC)(CCCC)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccs2)c2c1C(=O)NC2
Yield: 53.7 %

Procedure:
In a similar manner to Step 1 of Example 10, 7-amino-4-bromoisoindolinone (404 mg, 1.78 mmol) was dissolved in THF (20 mL), and the solution was treated with 2-(tributylstannyl)thiophene (1.13 mL, 3.56 mmol) and bis(triphenylphosphine)dichloropalladium (100 mg, 0.142 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 7-amino-4-(thiophen-2-yl)isoindolinone (220 mg, yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:15](=O)[C:14](=[CH:17]N(C)C)[CH2:13][C:7]2([O:11][CH:10](C)[CH2:9][O:8]2)[CH2:6]1)=[O:4].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[CH2:10]1[CH2:9][O:8][C:7]2([CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[C:15]3[N:46]=[C:44]([NH:43][C:33]4[CH:34]=[CH:35][C:36]([N:37]5[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]5)=[C:31]([O:30][CH3:29])[CH:32]=4)[N:45]=[CH:17][C:14]=3[CH2:13]2)[O:11]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COC(=O)C1CC2(CC(=CN(C)C)C1=O)OCC(C)O2
Solvent: O=[N+]([O-])O
Product: COC(=O)C1CC2(Cc3cnc(Nc4ccc(-n5cnc(C)c5)c(OC)c4)nc31)OCCO2

Procedure:
The title compound was prepared from methyl 9-[1-dimethylamino-methylidene]-8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid methyl ester (80 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (37 mg, 27%). MS ISP (m/e): 452.1 [(M+H)+]. mp 180-182° C.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCCC2)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (93%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:28])[N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.[Br:44][CH2:45][C:46](Br)=[O:47].C(OCC)C>ClCCl>[Br:44][CH2:45][C:46]([NH:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:28])[N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12])=[O:47]
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4ccc(O)cc4)C3=O)CS[C@H]12
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CBr)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4ccc(O)cc4)C3=O)CS[C@H]12

Procedure:
(E)-(6R,7R)-7-amino-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (736.0 mg, 1.83 mmol) was suspended in 20 ml dichloromethane and N,O-bis(trimethylsilyl)-trifluoroacetamide (1.94 ml, 7.32 mmol) was added. After 45 min bromoacetyl bromide (167 ml, 1.92 mmol) was added dropwise. After 1 h the reaction mixture was poured on 200 ml diethyl ether containing 160 ml water. After 15 min the solid material was collected by filtration, washed with diethyl ether and dried in high vacuum.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24]1[CH:39]=[CH:38][C:37](Br)=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([CH2:16][O:23][C:24]2[CH:39]=[CH:38][C:37]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[CH:36][C:25]=2[C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Na2CO3 (0.53 g, 5.00 mmol), followed by pyridin-4-ylboronic acid (0.34 g, 2.75 mmol) and Pd(Ph3P)4 (0.144 g, 0.125 mmol) were added to a mixture of benzyl 2-(benzyloxy)-5-bromobenzoate (may be prepared as described in Description 4; 1.0 g, 2.50 mmol) in 1,4-dioxane (25 ml) and water (5 ml) under nitrogen. After addition, the mixture was stirred at 90° C. for 4 hours. The reaction mixture was evaporated to give brown crude product, which was purified by chromatography (silica gel, 40 g, eluent: ethyl acetate/petroleum ether=1:2, 1.2 L) to yield the title compound as a white solid. 0.81 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:23][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3OC)c(C)c2)n1

Procedure:
Oxalyl chloride (126 μL; 1.5 mmol; 3 eq.), Intermediate 26 (120 mg; 0.5 mmol; 1 eq.), Intermediate 1 (82 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10) followed by precipitation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[N:7]2.[C:14]([O:18]CC)(=[O:17])[CH:15]=[CH2:16]>C1COCC1.CO.[Pd]>[CH3:13][O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([CH2:16][CH2:15][C:14]([OH:18])=[O:17])[CH:11]=[CH:10][CH:9]=2
Reactant: COc1cnc2cccc(Br)c2c1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc2cccc(CCC(=O)O)c2c1

Procedure:
This compound was synthesised from 5-bromo-3-methoxy-quinoline (5.0 g, 21 mmol; prepared as in DE 10316081) and ethyl acrylate (5 eq.) according to method G followed by hydrogenation over Pd/C in THF/MeOH 4:1. The hydrolysis was carried out according to method F. The product was isolated as a colourless solid (0.1 g).
Reaction SMILES: [CH3:1][C:2]([SH:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1CO>C(Cl)Cl>[CH3:1][C:2]([S:8][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(S)CC(=O)O
Reactant: COc1cc(OC)c(CO)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(SC(C)(C)CC(=O)O)c(OC)c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 3-methyl-3-sulfanylbutanoic acid (Sweetman et al, J. Med Chem.,14:868 (1971), the disclosure of which is incorporated herein by reference in its entirety) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5° C. (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (Munson et al., J. Org. Chem., 57, 3013 (1992), the disclosure of which is incorporated herein by reference in its entirety) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5° C. After the addition was complete, the mixture was stirred for an additional 5 minutes at 5° C. and the volatiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material evaporated in vacuo. The residue was treated with activated charcoal and recrystalized from diethyl ether/hexane. The product was isolated as a white solid in 70% yield (7 g). mp 103-105° C.; 1H NMR(CDCl3): δ6.12 (s, 2H), 3.80-3.85 (m, 11H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3): δ173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S-:11].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[S-]
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (Aldrich) (2.000 g, 12.27 mmol) in THF (25 mL) was added sodium thiomethoxide (Aldrich) (0.903 g, 12.88 mmol). The reaction mixture was stirred at rt under N2 for 3 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 5% to 10% acetone in hexanes) to afford the product as white solid (1.3 g). MS (ESI pos. ion) m/z: 174.9. 1H NMR (300 MHz, CDCl3) δ ppm 2.57 (s, 3H) 2.65 (s, 3H) 7.02 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[C:10]([C:15](=[O:17])[NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[N:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N(c1cccnc1)c1nccnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)c2nccnc2N(C(=O)OC(C)(C)C)c2cccnc2)n1
Temperature: 25 °C

Procedure:
3-(tert-Butoxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-carboxylic acid (405 mg, 80%, 1.02 mmol), 2-amino-4-methylthiazole (129 mg, 1.12 mmol), N,N-diisopropylethylamine (0.23 ml, 1.33 mmol) and TBTU (430 mg, 1.33 mmol) were dissolved in 1 ml DMF and stirred over night at room temperature. The reaction mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with 2N NaOH-solution, water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->40:60 gradient). The desired compound was obtained as a yellow foam (195 mg, 46%), MS: m/e=413.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][S:15]([C:18]3[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][NH2:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[N:10]=2)=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([O:44][Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH2:42]I)=[CH:37][C:36]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C@@H:41]([O:44][Si:45]([CH2:46][CH3:47])([CH2:48][CH3:49])[CH2:50][CH3:51])[CH2:42][NH:24][CH2:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([S:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:13][N:12]=3)(=[O:16])=[O:17])=[CH:26][CH:25]=2)=[CH:37][C:36]=1[NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC[Si](CC)(CC)OC(CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCN)cc3)no2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)O[C@@H](CNCCc1ccc(S(=O)(=O)Cc2noc(-c3ccc(OC)cc3)n2)cc1)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 57.3 %

Procedure:
A solution of the amine of Example 17 (0.90 g, 1.78 mmol), 1(S)-(4-benzyloxy-3-(methylsulfonamido)phenyl-1-triethylsiloxy-2-iodoethane (0.665 g, 1.60 mmol) and triethylamine (0.50 mL, 3.56 mmol) in THF (4 mL) was heated at 100° C. in a sealed tube for 60 h. The reaction mixture was cooled and evaporated in vacuo. The residue was flash chromatographed (silica gel; dichloromethane/ethyl ether/methanol: 25/25/0.75) to yield 0.740 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:29])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:29])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH3:20])[C:7]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Product: COCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
8-Cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido [2,3-d]pyrimidin-7-one (4.44 g, 14.54 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.94 g, 18.90 mmol) were dissolved in dichloromethane (100 mL) and stirred at ambient temperature for 12 hours. The solvent volume was reduced to approximately 50 mL and was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (2.51 g, 53.7%). 1H NMR δ (400 MHz, CDCl3) 8.93 (s, 1H), 7.78 (t, J=1.7 Hz, 1H), 5.99 (m, 1H), 4.46 (d, J=1.7 Hz, 1H), 3.53 (s, 3H), 2.96 (s, 3H), 2.23 (m, 2H), 2.12 (m, 2H), 1.93 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:26](=[O:28])[CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:29])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[C:26]([C:23]1[CH:24]=[CH:25][C:20]2[O:19][CH2:18][C:17](=[O:29])[N:16]([CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]3)[C:21]=2[CH:22]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)c1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: CC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl{1-[2-(6-acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 88) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:39])([F:38])[C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[F:20][C:21]([F:38])([F:39])[C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.5 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-[4-(trifluoromethyl)benzoyl]benzyl bromide (3.43 g) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. To the residue was added 4N-hydrogen chloride/ethyl acetate and the resulting precipitate was harvested by filtration. To this precipitate was added a saturated aqueous solution of NaHCO3 and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off to provide the title compound as colorless powder (1.57 g, 36%).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][CH3:20])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][CH3:20])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:11])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1cnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 245.3, 153 mg, 0.480 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 132 mg, 0.590 mmol, 1.10 equiv), EDC.HCl (204 mg, 1.01 mmol, 2.00 equiv, 95%) and 4-dimethylaminopyridine (131 mg, 1.02 mmol, 2.00 equiv, 95%) were added to the reaction. The resulting solution was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (2:1) as eluent. The crude product (˜150 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (28% CH3CN up to 43% in 7 min, up to 100% in 2 min, down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 62 mg (29%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.75-7.67 (m, 2H), 7.49-7.34 (m, 5H), 4.89-4.80 (m, 1H), 3.75-3.72 (m, 1H), 3.64-3.59 (m, 1H), 3.27-3.23 (m, 1H), 3.05-2.90 (m, 2H), 2.83 (q, 2H), 2.40 and 2.30 (2 singlets, amide rotamers, ArCH3, 3H), 2.27-1.97 (m, 6H), 1.90-1.70 (m, 4H), 1.40 (t, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M13) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (50 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:32]4[CH2:31][CH:30]5[O:37][CH:34]([CH2:35][CH2:36]5)[CH2:33]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: C1CC2CNCC1O2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 32.5 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (528 mg, 1.34 mmole) was combined with 8-Oxa-3-aza-bicyclo[3.2.1]octane (199 mg, 1.34 mmol) which gave 7-Cyclopentyl-2-[5-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (213 mg, 0.435 mmol) in 32.5% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.74 (m, 8H), 2.07 (m, 5H), 2.58 (m, 2H), 3.17 (s, 7H), 4.81 (dd, 1H), 6.48 (s, 1H), 7.79 (dd, 8.30 (s, 1H), 8.39 (d, 1H), 8.56 (d, 1H), 8.77 (s, 1H) MS m/z 490.5 (M+H)+.