Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:19]([OH:20])=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36]
Reactant: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate (14.63 g, 30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (2.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 6 h at ambient temperature. After the insoluble matter was filtered off, the solvent was concentrated in vacuo to give the crude product (7.58 g, 90% yield), which was used directly in next step without further purification.
Reaction SMILES: C([O:8][CH2:9][CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])C1C=CC=CC=1.CC(O)=O>CO>[OH:8][CH2:9][CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)N1CCOCC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CO)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
tert-butyl-3-(benzyloxy)-1-morpholino-1-oxopropan-2-ylcarbamate (31) (1.4 g, 4.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by MeOH (40 mL). The reaction flask was flushed with N2 (g) and charged with 10% Pd/C (290 mg). The flask was equiptpd with 2 H2 (g) balloons and stirred at rt for 30 min. AcOH (230 μL, 4.0 mmol, 1.0 equiv) was then added and the reaction was allowed to stir for 10 h. The solution was filtered through a pad of celite, washing with additional MeOH (200 mL). The solution was concentrated on a rotary evaporator, and dried under vacuum to give 1.2 g of crude material. The residue was purified by flash column chromatography (100% EtOAc) to give 970 mg (88%) of 32 as a colorless oil which crystallized to a white solid. Rf=0.26 (100% EtOAc); mp=45-47° C.; IR (film) 3418, 3315, 2972, 2927, 2859, 1706, 1631, 1444, 1166 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.87 (d, J=8.5 Hz, 1H, carbamate-NH), 4.67 (br d, J=4 Hz, 1H, Boc-NH—CH), 3.79 (br s, 2H, CH—CH2), 3.68-3.62 (m, 9H, morpholine CH2's & OH), 1.44 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 169.7, 155.7, 80.2, 66.8, 66.7, 64.0, 51.4, 46.3, 42.6, 28.4.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[NH2:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([CH2:30][CH3:31])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:19][C@@H:18]1[O:32][CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([NH:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([CH2:30][CH3:31])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:19][C@@H:18]1[O:32][CH2:33][CH3:34])=[O:7]
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)Cl
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)C(C)Oc1ccc(Cl)cc1Cl

Procedure:
In an analogous manner, from 2(RS)-(2,4-dichlorophenoxy)propionyl chloride (prepared from the acid) and 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine, there was obtained 5'-[2(RS)-(2,4 -dichlorophenoxy)propionamido]-2',5'-dideoxy-3'O-ethyl-5-ethyluridine of melting point 121°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][N:44]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(C)ccn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-4-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:49](=[O:50])C1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[C:49]3=[O:50])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCNCCNc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc([N+](=O)[O-])cc3)Cc3ccccc3)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN(CCCCc4ccc([N+](=O)[O-])cc4)Cc4ccccc4)c3c2)C1=O
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a solution of N-[3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N′-ethyl-ethane-1,2-diamine (20 mg in 3 mL dry methylene chloride) at 0° C. was added 9.6 mg N,N′-disuccinimidyl carbonate followed by triethylamine (0.110 mL of a 10% solution in methylene chloride) and the mixture stirred at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to provide the crude title compound (21 mg).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:13][C:14](=[CH2:16])[CH3:15].C([O-])(O)=O.[Na+]>O>[C:14]([O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])([CH3:16])([CH3:15])[CH3:13]
Reactant: O=C(O)C1CCCCC1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][OH:17])[N:8]=1.[H-].[Na+].[Cl:23][C:24]1[CH:29]=[N:28][CH:27]=[C:26]([Cl:30])[N:25]=1>C(O)(C)(C)C>[ClH:23].[Cl:30][C:26]1[N:25]=[C:24]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:9]2[N:8]=[C:7]([NH:6][C:5]([NH2:18])=[N:4][CH2:3][C:2]([F:20])([F:1])[F:19])[CH:12]=[CH:11][N:10]=2)[CH:29]=[N:28][CH:27]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(OCCCO)n1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cl
Product: NC(=NCC(F)(F)F)Nc1ccnc(OCCCOc2cncc(Cl)n2)n1
Reaction time: 18 h
Yield: 15.8 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-hydroxypropoxy)pyrimidine (293 mg.), a 50% w/w dispersion of sodium hydride in oil (72 mg.) and t-butanol (5 ml.) was stirred at 50° for 0.5 hours and then treated with 2,6-dichloropyrazine (165 mg.) and the resulting mixture was stirred at 50° for 18 hours. The mixture was evaporated to dryness and the residue stirred with a mixture of N aqueous hydrochloric acid and ether. The insoluble white solid was collected to give 6-chloro-2-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]-pyrimid-2-yloxy)propoxy]pyrazine hydrochloride (70 mg.), m.p. 167°-169°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:36][CH:37]1[CH2:40][NH:39][CH2:38]1>>[NH2:36][CH:37]1[CH2:40][N:39]([C:15]2[C:16]([F:18])=[CH:17][C:10]3[C:11]([CH:14]=2)=[N:12][C:13]2[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7](=[O:20])[C:8]=2[CH:9]=3)[CH2:38]1
Reactant: NC1CNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CC(N)C4)c(F)cc3cc2c1=O
Yield: 53.6 %

Procedure:
8-(3-Amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.7 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.88 g of 3-aminoazetidine dimethanesulphonate. After 1 recrystallization in 50 cm3 of ethanol, 1.05 g of 8-(3-amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 178°-180° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[N:6]1([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=CC(=O)Cl
Reactant: C1CCNCC1
Solvent: ClCCl
Product: C=CC(=O)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of acryloyl chloride (4.576 g, 50.558 mmol) in CH2Cl2 (50 ml) was added dropwise and very carefully piperidine (4.305 g, 50.558 mmol). The reaction flask was vented during the exothermic addition. After the addition was completed, the white slurry was stirred at 0° C. for 40 min and at RT for 1 h. The reaction was diluted with 70 ml CH2Cl2 and washed first with about 60 ml 2N HCl and then with about 60 ml of a mix of 2N NaOH and brine. The organic layer was dried over Na2SO4. The solution was evaporated by heating in a H2O bath at 60° C. without vacuum. Once most solvent had been evaporated off, dried the clear oil under high vacuum at RT for 30 min.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:16](=[O:25])[CH:17]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH3:18])[CH:7]=[CH:8][C:9]=1[O:10]C(OCC)=O>O.CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:16](=[O:25])[CH:17]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH3:18])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(OC(=O)OCC)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)NC(C)C(=O)c1ccc(O)c(Cl)c1
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A solution of 12.50 g of 85% potassium hydroxide (i.e. potassium hydroxide of purity about 85%, of which the main impurity is water) dissolved in a mixture of 20 ml of water and 30 ml of methanol was added dropwise, whilst ice-cooling, to a solution of 10.87 g of ethyl N-[2-(3-chloro-4-ethoxycarbonyloxyphenyl)-1-methyl-2-oxoethyl]carbamate [prepared as described in step (a) above] in 130 ml of methanol over a period of 5 minutes. The mixture was then stireed at room temperature for 20 minutes. At the end of this time, the mixture was concentrated by evaporation under reduced pressure and then acidified with 5% w/v aqueous hydrochloric acid. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried. The ethyl acetate of the solvent was then removed by evaporation under reduced pressure. The residue was recrystallized from a mixure of ethyl acetate and hexane, to give 6.12 g of the title compound as a yellowish-brown powder melting at 106°-108° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]([CH3:19])=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C.N1CCCCC1>[CH3:19][C:12]1[NH:11][CH:9]=[CH:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C=C(C)N
Reactant: O=C/C=C/c1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC=CC1c1ccccc1
Yield: 72.3 %

Procedure:
(E)-3-Phenyl-2-propenal (13.8 ml, 0.11 mol) and ethyl 3-amino-2-butenoate (12.9 g, 0.1 mol) were dissolved in 150 ml of absolute ethanol containing 0.5 ml of piperidine. The mixture was heated under reflux for 18 hours followed by removal of the solvent under vacuum to yield 17.6 g of ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate as a brown viscous oil.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14].CC(OC(N(C)C)N(C)C)(C)C>CC#N>[CH3:12][N:13]([CH:15]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH3:14]
Reactant: O=C1CCCc2ccccc21
Reactant: COC(OC)N(C)C
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CC#N
Product: CN(C)C=C1CCc2ccccc2C1=O

Procedure:
A solution of 3,4-dihydro-2H-naphthalen-1-one in MeCN and 20 eq. of DMF-DMA were stirred at 90° C. overnight. Thin layer chromatography indicated there is almost no desired product, hence 1.2 equivalents of Bredereck's reagent was added, and the reaction mixture stirred at 80° C. overnight. The solvent was removed under reduced pressure and the crude material was used for the next step with no further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:15])[CH2:9][CH2:8]2)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:15])[CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 0 °C

Procedure:
A mixture of 5-acetylamino-6-bromo-l-indanone (36.0 g, 0.13 mmol) and 6M aqueous hydrochloric acid (800 mL) was refluxed for 1 h. The homogenous solution was then cooled to 0° C. and adjusted to pH 8 with 10M aqueous NaOH (~480 mL). The precipitate formed was collected, washed with water and dried under vacuum to afford 30.0 g (quantitative) of the title compound as a light brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]([CH3:26])[CH3:25])[N:3]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]([CH3:26])[CH3:25])[N:3]=1
Reactant: CCOC(=O)c1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C(C)C)nc(N)c(CO)c1-c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
100 ml (0.35 mol) of a 3.5M solution of sodium bis-(2-methoxy-ethoxy)-dihydroaluminate in toluene are initially introduced under argon into 100 ml of tetrahydrofuran p.a. 63 g (175 mmol) of the compound from Example III dissolved in 700 ml of tetrahydrofuran are added dropwise and the mixture is subsequently stirred at 30° C. for 1 h. 2 l of water are cautiously added dropwise. The phases are separated and the aqueous phase is washed twice with 700 ml of ethyl acetate. The combined organic phases are washed with 500 ml of saturated sodium chloride solution and dried using sodium sulphate. The solution is filtered and concentrated in vacuo. The residue is chromatographed in a column (φ 6 cm) on 400 g of silica gel 230-400 mesh using petroleum ether/ethyl acetate (1:1). The eluate is concentrated in vacuo and the residue is thoroughly stirred in ether/petroleum ether.
Reaction SMILES: [N:1]#[C:2][NH2:3].C(OC(=O)[N:10]([CH2:23][CH3:24])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)(C)(C)C.Br[CH2:27][C:28]([C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)=[O:29]>>[NH2:1][C:2]1[N:3]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][CH2:23][CH3:24])=[CH:19][CH:18]=2)[S:22][C:27]=1[C:28]([C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)=[O:29]
Reactant: CCN(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: N#CN
Product: CCNCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc4c(c3)OCCO4)s2)cc1

Procedure:
This compound was prepared from cyanamide, ethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester of Example 129D and 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone (Maybridge Chemical) following a procedure similar to Example 133. Mass spectrum (ES) MH+=441.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N(C(C)C)CC)(C)C.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[B-](F)(F)(F)F.CCCC[P+](C1SC(C(OC)=O)=C(C(OC)=O)S1)(CCCC)CCCC.[C:73]([O:77][CH2:78][C@@H:79]([NH2:94])[CH2:80][CH2:81][N:82]1[CH2:85][CH:84]([O:86][C:87]2[CH:92]=[CH:91][C:90]([F:93])=[CH:89][CH:88]=2)[CH2:83]1)([CH3:76])([CH3:75])[CH3:74]>CN(C)C=O>[C:73]([O:77][CH2:78][C@@H:79]([NH:94][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:80][CH2:81][N:82]1[CH2:83][CH:84]([O:86][C:87]2[CH:88]=[CH:89][C:90]([F:93])=[CH:91][CH:92]=2)[CH2:85]1)([CH3:76])([CH3:74])[CH3:75]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(C)(C)OC[C@@H](N)CCN1CC(Oc2ccc(F)cc2)C1
Agent: CCCC[P+](CCCC)(CCCC)C1SC(C(=O)OC)=C(C(=O)OC)S1
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: COc1cc(C(=O)N[C@@H](CCN2CC(Oc3ccc(F)cc3)C2)COC(C)(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3,4,5-trimethoxy-benzoic acid (0.246 g, 1.16 mmol) and diisopropylethylamine (0.62 ml, 3.47 mmol) in dry dimethylformamide (10 ml) is treated with [(benzotriazol-1-yloxy)-dimethylamino methylene]-dimethyl-ammonium; tetrafluoro borate (0.32 g, 1.0 mmol). The reaction mixture is stirred at ambient temperature for 5 minutes, then (S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.968 mmol) is added and the reaction mixture stirred for 20 hours. The dimethylformamide is evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution 50% ethylacetate/hexane to 100% ethylacetate) to afford N-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide [MH]+ 505.3.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][S:10][CH3:11].[CH3:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.C(OCC)C>ClC(Cl)C>[Cl-:1].[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[S+:10]([CH3:11])[CH3:9])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC
Reactant: Cc1cc2ccccc2[nH]1
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: Cc1[nH]c2ccccc2c1[S+](C)C
Product: [Cl-]
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
N-chlorosuccinimide (3.85 g, 29.35 mmole) was suspended in dichloroethane (40 ml) under a nitrogen atmosphere and cooled to −10° C. using an ice-salt-acetone bath. Dimethylsulfide (3 ml) was slowly added with stirring over a period of about 5 minutes. The mixture was stirred at this temperature for 10 minutes beyond the addition, at which time the ice-salt-acetone bath was replaced by a dry-ice acetone bath and the temperature was lowered to −50° C. To this solution was added 2-methylindole (3.85 g, 29.35 mmole) dissolved in dichloroethane (40 ml) slowly with stirring. The reaction mixture was stirred while allowing the temperature to reach 20° C. over about an hour. Diethyl ether (90 ml) was added with stirring and the precipitate which formed was filtered, washed well with ether, and dried overnight in a vacuum oven at room temperature. The free-flowing powder of (2-methyl-1H-indol-3-yl)-dimethylsulfonium chloride thus obtained was used without further purification in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13](Cl)=[O:14])[N:7]2[CH3:12].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=23)=[CH:19][C:18]=1[OH:46].C(N(CC)C(C)C)(C)C>ClCCl>[OH:46][C:18]1[CH:19]=[C:20]([C:23]2[N:24]=[C:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=23)[CH:21]=[CH:22][C:17]=1[NH:16][C:13]([C:6]1[N:7]([CH3:12])[C:8]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)=[O:14]
Reactant: COc1cccc2c1cc(C(=O)Cl)n2C
Reactant: Cc1nccn2c1c(-c1ccc(N)c(O)c1)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc2c1cc(C(=O)Nc1ccc(-c3nc([C@H]4CC[C@H](N5CCN(C)CC5)CC4)n4ccnc(C)c34)cc1O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 4-methoxy-1-methyl-1H-indole-2-carbonyl chloride (described in example 2g) (0.048 mmol, 10.64 mg) was added to a solution of 2-amino-5-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenol (116 mg impure material) and N,N-diisopropylethylamine (0.145 mmol, 24 μl) in dichloromethane at 0° C. The mixture was stirred at room temperature for one hour. Purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/methanol 5/1) followed by purification with HPLC (column: X-bridge; eluens acetonitrile/methanol/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and basified with aqueous sodium carbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give N-(2-hydroxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (7 mg)