Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:65][C:66]1[CH:78]=[CH:77][C:69]([CH2:70][C@@H:71]2[CH2:76][CH2:75][CH2:74][NH:73][CH2:72]2)=[CH:68][CH:67]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([N:73]2[CH2:74][CH2:75][CH2:76][C@@H:71]([CH2:70][C:69]3[CH:68]=[CH:67][C:66]([F:65])=[CH:78][CH:77]=3)[CH2:72]2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (80 mg, 240 μmol) in methylene chloride (5 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (151 mg, 290 μmol) and triethylamine (77 μL, 550 μmol) and stirred for 5 minutes. A solution of the (S)-3-(4-flourobenzyl)-piperdine prepared above in methylene chloride (5 mL) was added and the mixture was stirred at room temperature. After 18 h , the mixture was washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes) to provide the product as a gum (100 mg, 82%). 1H NMR (300 mHz, CD3OD) δ7.32-6.95 (7H), 4.42-4.30 (1H), 3.90-2.48 (14H), 1.80-1.62 (3H), 1.40 (bs, 9H), 1.29 (d, 3H); mass spec. (ES+) m/z 510.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)N2CCOCC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-chlorosulfonyl-piperidine-1-carboxylic acid tert-butyl ester (295 mg) in dichloromethane stirring at 0° C. was added triethylamine (96 μL) and morpholine (55 μL). The reaction mixture was stirred overnight then quenched with water and extracted into dichloromethane. The combined organics were washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 4-(morpholine-4-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (120 mg).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]#[C:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.I[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]#[C:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH:16]=[CH:17][C:18]=3[O:19][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: CCCCCCCCCI
Reactant: COC(=O)c1ccc(C#Cc2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
75 mg (2.6 mmol) of sodium hydride (80% in oil) and 10 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 1 g (2.6 mmol) of methyl 4-[3-(1-adamantyl)-4-hydroxyphenylethynyl]benzoate dissolved in 70 ml of DMF was added dropwise and stirring was carried out at room temperature until gas evolution had ceased. 610 μl (3.1 mmol) of 1-iodononane were then added dropwise and stirring was carried out at room temperature for four hours. The reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulphate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[O:31]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:40]4[CH2:41][CH2:42][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1COCCOCCOCCN1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCOCCOCCOCC1

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 1,4,7-trioxa-10-aza cyclododecane was converted to 37.5 mg of the title compound(free base) and mass spectrum (electrospray, m/e): M+H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 584.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([OH:28])(=O)=[O:26].C(Cl)(=O)C([Cl:32])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([Cl:32])(=[O:28])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the 5-chloro-2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonic acid (9.52 g, 21.4 mmol) in 100 mL of dichloromethane at 0° C. was added oxalyl chloride (5.61 mL, 64.3 mmol). Dimethylformamide (0.2 mL) was added, and the reaction was allowed to warm to room temperature. After 24 hours, another portion of oxalyl chloride (3.0 mL) was added, and the reaction was stirred for an additional 16 hours. The mixture was concentrated in vacuo to provide a yellow foam. Proton NMR for the product was consistent with the titled compound. ESI+MS: 426.2 [M−Cl]+.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:37])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:35]=[C:34]([F:36])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:37])[CH:3]=1
Reactant: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (578 mg, 1 mmol) in methylene chloride (10 ml) containing TFA (4 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was suspended in water. The aqueous layer was adjusted to approximately pH 10 and was extracted with methylene chloride. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with ether and dried under vacuum to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (110 mg, 23%).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:16][CH:13]1[CH2:14][CH2:15][CH:10]([C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH2:11][CH2:12]1
Reactant: CC#CCO
Reactant: CC1CCC(c2nc(S(C)(=O)=O)ns2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCC(C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
400 mg of 3-methylsulfonyl-5-(4-methylcyclohexyl)-1,2,4-thiadiazole and 129 mg of 2-butyn-1-ol were dissolved in 3 ml of N,N-dimethylformamide, 80 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 258 mg of 5-(4-methylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (12)).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[O:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1)C=C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[O:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH:6]=[C:5]2[NH2:4])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: C=CCNc1cc(NCc2ccc(C)o2)nc2ccc(Cl)cc12
Product: Cc1ccc(CNc2cc(N)c3cc(NCc4ccccc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=359.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4-diamine and benzylamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].[CH3:32][O:33][C:34]([C:36]1[CH:37]=[CH:38][C:39]([N:42]([CH2:55][CH2:56][CH3:57])[S:43]([C:46]2[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=2)[C:49](O)=[O:50])(=[O:45])=[O:44])=[N:40][CH:41]=1)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[CH3:25][O:24][C:22]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]([C:6]3[C:5]4[CH2:28][CH2:29][CH2:30][CH2:31][C:4]=4[S:3][C:2]=3[NH:1][C:49]([C:48]3[CH:47]=[C:46]([S:43]([N:42]([CH2:55][CH2:56][CH3:57])[C:39]4[CH:38]=[CH:37][C:36]([C:34]([O:33][CH3:32])=[O:35])=[CH:41][N:40]=4)(=[O:45])=[O:44])[CH:54]=[CH:53][CH:52]=3)=[O:50])=[O:8])=[CH:15][CH:14]=2)=[CH:27][CH:26]=1)=[O:23]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
To a mixture of 100 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 2 mL of DMF were added 105 mg of 3-{[5-(methoxycarbonyl)pyridin-2-yl](propyl)sulfamoyl}benzoic acid, 110 mg of HATU, and 0.060 mL of N-ethyl diisopropylamine, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 110 mg of methyl 6-[{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}(propyl)amino]nicotinate as a pale brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:10]([CH2:11][C:12](=[O:27])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](OCC)=[O:29].[O-]CC.[Na+]>C1COCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH:14]([CH2:13][C:12](=[O:27])[C:11]2=[CH:28][OH:29])[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (5.08 g, 12.2 mmol) was dissolved in THF/ethanol (40 mL, 1/1, v/v). Ethyl formate (9.84 mL, 122.4 mmol) was added followed by sodium ethoxide (12 mL of 21% solution in ethanol). The resulting mixture was stirred at room temperature for 30 minutes then heated to 60° C. for 30 minutes after which the solution was cooled back to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 5.43 g (quantitative) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=2.114, method [1], MS(ESI) 465.0 (M+Na).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:21][C:19]1[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNC(=S)NC2CC3C=CC2C3)o1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 5-nitro-2-furaldehyde (59 μL, 0.56 mmol) similar to Example 3 and isolated as a dark yellow solid (4 mg, 2%). 1H NMR (CDCl3): 10.02 (s, 1H), 7.74 (s, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.39 (d, J=3.9 Hz, 1H), 6.88 (d, J=3.9, 1H), 6.26-6.14 (m, 2H), 4.26-4.22 (m, 1H), 3.07 (s, 1H), 2.99 (s, 1H), 1.94-1.87 (m, 1H), 1.68 (d, J=9.3 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.48-1.42 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:23])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:23])[NH:1]3)[CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: CN(C)CCc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CN(C)CCc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of {2-[3-(1H-indol-4-yl)-phenyl]-ethyl}-dimethyl-amine (600 mg, 2.2 mmol) in t-BuOH:ethanol:acetic acid (14.5 mL:8.8 mL:10.5 mL) was added pyridinium tribromide (2.3 g, 6.6 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (9.24 mL). Water (0.32 mL) and zinc dust (2.2 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was dissolved in methanol (10 mL) and hydrogenated using 10% Pd—C for overnight. The reaction was filtered through celite and the filtrate was concentrated. The residue was purified on a silica gel column to give 4-[3-(2-dimethylamino-ethyl)-phenyl]-1,3-dihydro-indol-2-one
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][OH:30]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:27][CH2:28][CH2:29][OH:30])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCO)CO2

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-aminoethanol (0.5 ml), ACN (3 ml). 1H-NMR (400 MHz, CD3OD): δ 7.47 (1H, d, J 2), δ 7.42 (1H, dd, J 8, 2), δ 7.07 (1H, d, J 8.0), δ 4.43 (1H, dd, J 12, 2.4), δ 4.37 (1H, m)), δ 4.09 (1H, dd J 12, 7.2), δ 3.68 (2H, t, J 5.6), δ 3.07 (3H, s), δ 2.94 (2H, m), 2.80 (2H, m) ppm (J-values are in Hz and shifts relative to solvent-peak at 3.31 ppm).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.Cl.O1CCOCC1>O=[Pt]=O.CC(O)=O>[CH2:1]1[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[C:3](=[O:10])[NH:2]1
Reactant: O=C1NCc2ccncc21
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C1NCC2CCNCC12
Yield: 138.3 %

Procedure:
1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one (19.6 g, 0.146 mol) was placed into a hydrogenation reactor together with 250 mL AcOH and 1 g of PtO2 (Colonial Metals). An H2 pressure of 60 PSI was applied and the mixture hydrogenated until a pressure of 26 PSI was measured. The reaction mixture was filtered and the solvent evaporated. At the end of the evaporation, 4 N HCl in 1,4-dioxane (50 mL, 0.2 mol) was added. The solvent was evaporated to dryness. Ether (800 mL) was added and the mixture was stirred and filtered. The filter, a white solid, was dried to give 28.3 g of the desired product. 1H NMR (300 MHz, d6-DMSO) δ=9.42 (br s, 1H), 8.33 (br s, 1H), 7.88 (s, 1H), 3.44-3.25 (m, overlaps with water peak, observed integral of 6H includes water), 3.11-3.01 (m, 2H), 2.88-2.76 (m, 2H), 2.64 (br t, 1H), 2.55-2.45 (m, 3H) 1.90-1.75 (m, 1H), 1.61-1.42 (m, 1H). LCMS: 1.0 min, M+H=144.1 u/e.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[F:8][C:9]([F:21])([F:20])[CH2:10][CH2:11][S:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:14])=[O:13].[H-].[Na+].Cl>CS(C)=O>[F:21][C:9]([F:8])([F:20])[CH2:10][CH2:11][S:12]([CH:15]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[CH:2])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:14]
Reactant: C#CCCCCCl
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 1.0 g of 6-chloro-1-hexyne and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 0.3 g of sodium hydride (60% in oil) was added at room temperature. The mixture was stirred at room temperature for 12 hours, at 60° C. for 2 hours and then at 90° C. for 10 hours. The reaction mixture was allowed to stand near room temperature, and 10% hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.50 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-7-octynoate (hereinafter referred to as the present compound (1)).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:27])[C:18]([OH:26])=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].Cl.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[C:34]([N:40]2[C:44]([CH3:45])=[CH:43][N:42]=[N:41]2)[CH:33]=1.C(N(CC)CC)C>C(O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:27])[C:18]=2[OH:26])=[O:23])=[C:34]([N:40]2[C:44]([CH3:45])=[CH:43][N:42]=[N:41]2)[CH:33]=1
Reactant: Cc1cnnn1-c1cc(F)ccc1CN
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylat (30 mg, 0.076 mmol), (4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine, bis-hydrochloride salt (42.7 mg, 0.153 mmol) and triethylamine (0.1 ml, 0.717 mmol) in ethanol (2 mL) was heated at 90° C. for 18 h. The reaction mixture was then cooled, concentrated and purified on preparative reversed phase HPLC to afford the title compound (10 mg, 21% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 1.66-1.77 (m, 2 H) 1.90-2.01 (m, 2 H) 2.14-2.24 (m, 2 H) 2.27 (s, 3 H) 2.39-2.47 (m, 2 H) 2.50 (br. s., 1 H) 2.89 (s, 3 H) 3.19 (s, 3 H) 4.15 (d, J=3.97 Hz, 2 H) 4.23 (d, J=6.41 Hz, 2 H) 6.99 (dd, J=8.24, 2.44 Hz, 1 H) 7.26-7.33 (m, 2 H) 7.62-7.68 (m, 2 H) 8.86 (t, J=6.10 Hz, 1H) 11.73 (br. s., 1 H). LCMS (M+H)=553.22. HPLC purity: >95%.
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15]I>>[P:1]([O:13][CH2:15][Cl:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: ClCI
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Yield: 343.6 %

Procedure:
The tetrabutylammonium salt of bis-tert butyl phosphate (57 g, 0.126 mol, Digital Specialty Chemicals) and chloroiodomethane (221 g, 1.26 mol) were stirred at room temperature for four hours and then the volatiles were removed in vacuo. 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate and final removal of volatiles using a vacuum pump provided di-tert-butyl chloromethyl phosphate (112 g), typically as a light yellow or brown oil, which was utilized in the next step without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].CC(C)=O.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[I:25]>O>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([O:24][CH2:2][CH2:3][CH3:4])[CH:21]=[CH:20][C:19]=1[I:25]
Reactant: COC(=O)c1cc(O)ccc1I
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCOc1ccc(I)c(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
2.97 mL (32.7 mmol) 1-bromopropane and 299 mg (1.80 mmol) KI are added to a mixture of 3.39 g (24.5 mmol) K2CO3 and 200 mL acetone. The mixture is stirred for 30 min at reflux. Subsequently, 5.00 g (18.0 mmol) methyl-5-hydroxy-2-iodobenzoate are added and the resulting mixture is refluxed for 2 h. One additional equivalent of 1-bromopropane and of K2CO3 is added and refluxing is continued for 12 h. Water is added and the mixture is extracted with EtOAc. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 100/0→60/40). The product is used without further characterization.