Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:29][O:30][CH3:31])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Br)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1ccc(Cl)cc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-bromo-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide (1.00 g, 2.49 mmol) and K2CO3 (1.72 g, 12.4 mmol) in 8 mL anhydrous THF was added chloromethyl methyl ether (299 mg, 3.73 mmol). The resultant heterogeneous solution was stirred for 60 minutes at ambient temperature and the solids were subsequently removed via filtration. The filtrate was subsequently concentrated in vacuo and the residue was dissolved in EtOAc. The organics were washed with saturated Na2CO3, dried over MgSO4, and evaporated in vacuo. The resultant residue was then purified via automated silica gel chromatography to afford the desired protected sulfonamide: MS (ES) M+H expected 446.0, found 446.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C([O-])(O)=O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:21]([O:20][C:18]([NH:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 60 °C
Yield: 92 %

Procedure:
To a 1 L 3-necked flask equipped with a thermometer and a magnetic stirrer were added 4.90 g of L-glutamic acid γ-methyl ester (Sigma) and 200 mL of water. The solution was heated to 60° C., treated with 6.40 g of NaHCO3 followed by 5.20 mL of benzyl chloroformate (Aldrich) and allowed to cool to RT with vigorous stirring. After 4 h the reaction mixture was extracted with ethyl ether (4×100 mL) and the ether extracts were discarded. The aqueous solution was acidified to a congo red endpoint by addition of concentrated HCl. An oily emulsion resulted which was extracted with CH2Cl2 (4×60 mL). The combined organic extracts were washed with 0.05 N aqueous HCl (2×60 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford 8.23 g (92%) of N-((benzyloxy)carbonyl)-5-O-methyl-L-glutamic acid as a white crystalline solid, m.p. 61-63° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:30][CH2:31][N:32]([CH2:7][C:6]4[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:33][CH2:34]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:15]1
Reactant: Fc1ccc(C(F)(F)F)c(CCl)c1
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(Cc3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a light yellow solid (34% yield). 1H NMR (300 MHz, CDCl3) δ 7.98, 7.88, 7.55-7.65, 7.2, 6.93, 3.68-3.85, 3.50, 2.60, 1.70, 1.25, 0.65, 0.40, 0.09. MS (ES+) m/z 466 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]([Mg]Br)#[CH:20]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:19]#[CH:20])[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)c1cc(C=O)ccc1N1CCCCC1
Product: C#CC(O)c1ccc(N2CCCCC2)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1 g (4 mmol) of 3-tert-butyl-4-piperidin-1-ylbenzaldehyde with 12 ml (6 mmol) of a 0.5M solution of ethynylmagnesium bromide. 890 mg of 1-(3-tert-Butyl-4-piperidin-1-ylphenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=82%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].[C:22]1([CH2:32][CH2:33][NH2:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:34][CH2:33][CH2:32][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Reactant: NCCc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNCCc1cccc2ccccc12
Temperature: 25 °C
Yield: 80.1 %

Procedure:
(2S,4S)-2-Formyl-4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (1) (1.84 g) in dichloromethane(20 ml) was added dropwise over 10 minutes to a mixture of 2-naphthalen-1-ylethylamine (1.0 g),. sodium triacetoxyborohydride(1.36 g) and 4A powdered molecular sieve (3.0 g) in dichloromethane (130 ml) cooled to −20° C. and stirred under an argon atmosphere. After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for a further 18 hours. The molecular sieves were filtered off and the fitrate stirred with saturated aqueous sodium bicarbonate solution( 100 ml) for 5 minutes. The mixture was separated, the organic phase dried over magnesium sulphate and applied to a silica flash column which was then eluted with 1.Ethyl acetate/Hexane(50:50), 2.Ethyl acetate/Hexane(80/20), 3.Ethyl acetate to give (2S,4S)-4-BOCsulfanyl-2[(2-naphthalen-1-ylethylamino)-methyl]pyrrolidine-1-carboxylic acid allyl ester (2) (2.2 g) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)OCC)cn2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)O)cn2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (308 mg) in dioxane (7.4 mL) was added 1N sodium hydroxide (2.21 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O(37 mL) and acidified with 1N hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride (214 mg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])=[CH:10][CH:11]=1.Cl.[C@@H:21]1([O:52][P:53]([OH:56])([OH:55])=[O:54])[C@@H:26]([O:27][P:28]([OH:31])([OH:30])=[O:29])[C@H:25]([O:32][P:33]([OH:36])([OH:35])=[O:34])[C@@H:24]([O:37][P:38]([OH:41])([OH:40])=[O:39])[C@@H:23]([O:42][P:43]([OH:46])([OH:45])=[O:44])[C@H:22]1[O:47][P:48]([OH:51])([OH:50])=[O:49]>O>[CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])=[CH:8][CH:7]=1.[CH:23]1([O:42][P:43]([OH:46])([OH:45])=[O:44])[CH:24]([O:37][P:38]([OH:40])([OH:41])=[O:39])[CH:25]([O:32][P:33]([OH:35])([OH:36])=[O:34])[CH:26]([O:27][P:28]([OH:31])([OH:30])=[O:29])[CH:21]([O:52][P:53]([OH:56])([OH:55])=[O:54])[CH:22]1[O:47][P:48]([OH:50])([OH:51])=[O:49]
Reactant: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Agent: CCCCNc1ccc(C(=O)OCCN(C)C)cc1
Agent: Cl
Solvent: O
Product: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O
Reaction time: 0.5 h

Procedure:
1.0 g tetracaine hydrochloride (3.33 mmol) was dissolved in 40 mL water and with vigorous stirring, 20.5 mL of the phytic acid solution of Example 1 was added. After another 30 min of stirring, the precipitate was centrifuged and washed with water. The final products were in the form of white powder. The solubility of the complex in different buffers is shown below.
Reaction SMILES: C(O)(=O)C1C=CC(OC)=C(OC)C=1.COC1C=C(C=CC=1OC)C(OC)=O.[BH4-].[Na+].CS(CC(O)C1C=CC(OC)=C(OC)C=1)=O.N(CCC#N)C1C=CC=CC=1.C[O-].[Na+].[CH3:60][O:61][C:62]1[CH:63]=[C:64]([CH:77]=[CH:78][C:79]=1[O:80][CH3:81])[CH2:65][C:66](=[CH:69]NC1C=CC=CC=1)[C:67]#[N:68].[NH2:82][C:83]([NH2:85])=[NH:84]>CO.Cl.CN(C)P(N(C)C)(N(C)C)=O>[NH2:84][C:83]1[N:85]=[C:67]([NH2:68])[C:66]([CH2:65][C:64]2[CH:77]=[CH:78][C:79]([O:80][CH3:81])=[C:62]([O:61][CH3:60])[CH:63]=2)=[CH:69][N:82]=1
Reactant: N=C(N)N
Reactant: COc1ccc(CC(C#N)=CNc2ccccc2)cc1OC
Agent: COC(=O)c1ccc(OC)c(OC)c1
Agent: COc1ccc(C(=O)O)cc1OC
Agent: COc1ccc(C(O)CS(C)=O)cc1OC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OC

Procedure:
Veratric acid is esterified by refluxing in methanol using hydrochloric acid as catalyst. The resulting methyl 3,4-dimethoxybenzoate is converted under the conditions of Example 103 to ω-(methylsulfinyl) 3,4-dimethoxyacetophenone. This is reduced with sodium borohydride under the condition of Example 104 to β-hydroxy-β-(3,4-dimethoxyphenyl)ethyl methyl sulphoxide, which is then allowed to react with β-anilinopropionitrile in hexamethylphosphoramide containing sodium methylate according to Example 105. The resulting α-(3,4-dimethoxybenzyl)-β-anilinoacrylonitrile is condensed with guanidine according to Example 106 to give 2,4-diamino-5-(3',4'-dimethoxybenzyl) pyrimidine, m.p. 224°-229° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4c(c3)CC(=O)N4)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one (63.1 mg, 0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 30 mg (34%). LCMS E-S (M+H)=471.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 3.40 (br. s., 2H), 4.41 (d, J=4.6 Hz, 2H), 5.25-5.41 (m, 1H), 5.91 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 8.08-8.21 (m, 3H), 8.34 (s, 1H), 8.96 (br. s., 1H), 10.64 (s, 1H), 11.58 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[C:3](O)=O.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]([C:3]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)([CH3:8])[C:6]#[CH:7]
Reactant: NNC(N)=S
Reactant: C#CC(C)(C)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(C)(C)c1nnc(N)s1

Procedure:
Commercially available, 2,2-dimethylbut-3-ynoic acid (Betapharma), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[N:6][CH:7]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=3)=[CH:7][N:6]=2)=[CH:9][C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11]1
Reactant: COC(=O)c1cc(-c2ccc(Br)cn2)n(-c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cn2)n(-c2ccccc2Cl)n1
Temperature: 120 °C

Procedure:
Methyl 5-(5-bromopyridin-2-yl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (200 mg, 0.51 mmol), 3-(methylsulfonyl)phenylboronic acid (120 mg, 0.60 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (11) dichloromethane adduct (20 mg, 24 μmol), and K2CO3 (0.45 mL of a 3.5M aqueous solution, 1.6 mmol) were combined in DME (2.5 mL) in a microwave reaction vessel. The dark mixture was heated at 120° C. for 5 minutes. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was removed and extracted with additional EtOAc. The combined organics were dried over Na2SO4, treated with some decolorizing carbon and filtered through a pad of Celite. Concentration of the filtrates under reduced pressure and purification by flash column chromatography eluting with 0% to 50% MeCN/CH2Cl2 afforded methyl 1-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate as a pale yellow foam. This material was carried on to the subsequent step. MS(ES): 468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: C1COCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), HOBt (3 mg, 0.1 eq.), EDAC.HCl (44 mg, 1.2 eq.) and morpholine (18 mg, 1.1 eq.) in DMF (2 mL) at rt was added TEA (0.067 mL, 2.5 eq.). After stirring at rt for 7 days, the reaction was concentrated, diluted with DCM (10 mL) and methanol (0.5 mL) and then mixed with solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as a reddish-orange solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (58 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (140 mg, 56%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.94 (d, 2H), 4.04 (t, 2H), 3.79 (m, 2H), 3.57 (m, 2H), 3.24 (d, 2H), 2.75 (s, 3H), 2.63 (t, 2H), 2.54 (m, 4H), 2.12 (m, 2H), 2.01 (m, 2H), 1.88 (m, 2H), 1.80 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]([O:29][C:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[NH:26][C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH3:19])[C:11]=4[CH:10]=3)=[CH:5][CH:4]=2)[CH2:36][CH2:35]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 1.6 g (4 mmol) [6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine (for the preparation see Example 9, Step 9.3 of WO 03/013541 A1) in 50 ml DMF is treated with 1.56 g (8.4 mmol) N—BOC-piperazine and 2.76 g (20 mmol) anhydrous potassium carbonate and the mixture heated to 65° C. for 1 hour. The reaction mixture is cooled and the inorganic salts removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). The DMF is evaporated under reduced pressure and the residue purified through flash chromatography using first dichloromethane/ethanol 95:5 and then dichloromethane/ethanol 9:1. The title compound is obtained as a solid; m.p. 244-246° C.; MS-ES+: (M+H)+=513; TLC Rf(dichloromethane/ethanol 9:1) 0.46.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][C@@H:17]4[CH2:19][C@H:14]3[CH2:15][N:16]4[S:20]([CH3:23])(=[O:22])=[O:21])[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][C@@H:17]5[CH2:19][C@H:14]4[CH2:15][N:16]5[S:20]([CH3:23])(=[O:21])=[O:22])[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2C[C@@H]3C[C@H]2CN3S(C)(=O)=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)n(C)c2n1
Yield: 81.6 %

Procedure:
A mixture of 2-chloro-8-((1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.34 mmol), 2-ethyl-1H-benzoimidazole (59 mg, 0.40 mmol), Pd2dba3 (9 mg, 0.009 mmol), Xphos (18 mg, 0.036 mmol) and cesium carbonate (165 mg, 0.51 mmol) in 1,4-dioxane (3 mL) was purged with argon gas then subjected to microwave irradiation at 150° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH 100:0 to 99:1 to 98:2) to afford 553 as a white solid (153 mg, 82%). LCMS (Method I): RT=2.53 min, M+H+=552. 1H NMR (CDC3, 400 MHz) δ 8.01 (m, 1 H); 7.77 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 5 H); 4.06 (d, J=13.6 Hz, 1 H); 3.96 (d, J=13.6 Hz, 1 H); 3.87 (m, 7 H); 3.65 (d, J=9.5 Hz, 1 H); 3.61 (bs, 1 H); 3.37 (q, J=7.5 Hz, 2 H); 3.27 (dd, J=9.5, 2.3 Hz, 1 H); 3.02-2.93 (m, 2 H); 2.91 (s, 3 H); 1.99 (d, J=10.2 Hz, 1 H); 1.79 (d, J=10.2 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]1.[F:31][C:32]1([F:39])[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[F:31][C:32]1([F:39])[CH2:37][CH2:36][C:35]([C:21]2([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)([OH:38])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(C2(O)CCC(F)(F)CC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A solution of LDA prepared from diisopropylamine (304 mg, 3.00 mmol) and butyllithium (1.20 mL, 3.00 mmol) in THF was added to a cold (−78° C.) solution of tert-butyl cyclopropanecarboxylate (427 mg, 3.00 mmol) in THF (2 mL), and the mixture was stirred at −78° C. for 1 h. A solution of 4,4-difluorocyclohexanone (268 mg, 2 mmol) in THF (0.5 mL) was added dropwise and the mixture was stirred at −78° C. for 2 h and allowed to warm to rt overnight. The crude product was purified by silica gel FCC (DCM) to afford tert-butyl 1-(4,4-difluoro-1-hydroxycyclohexyl)cyclopropanecarboxylate as a clear oil (0.273 g). 1H NMR (500 MHz, CDCl3) δ ppm 2.12-2.30 (2H, m), 1.79-1.96 (4H, m), 1.48-1.53 (2H, m), 1.41-1.47 (9H, m), 1.21-1.34 (1H, m), 1.11-1.17 (2H, m), 0.90-0.97 (2H, m).