Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1.CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[NH:25][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[C:21]=2[N:22]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65) (100 mg, 0.26 mmol) in pyridine (2 mL) was added methyl chloroformate (28 mg, 0.29 mmol, Aldrich) at 0° C. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with 1 N NaOH and water. The EtOAc layer was separated, dried over Na2SO4, filtered and evaporated in vacuum. Purification of the residue by silica gel chromatography with gradient: 40 to 80% EtOAc in hexanes gave the title compound as an off white solid. MS (ESI, pos. ion.) m/z: 447 (M+1).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].Cl.[CH3:20][S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22]>>[CH:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:28][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][N:26]=2)[CH2:30][CH2:31]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 44 %

Procedure:
Prepared in analogy to example 1 (b) from rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (Example A10) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 44%). MS (m/e): 502.1 (M+H+, 99%), 519.3 (M+NH4+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH2:20])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH:20][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2cccc(Cl)c2)c2cc([N+](=O)[O-])ccc21
Reaction time: 6 h
Yield: 36 %

Procedure:
3-Amino-5-nitroindazole-1-carboxylic acid tert-butyl ester (600 mg, 2 mmol) was dissolved in dry pyridine (15 mL) under nitrogen. The solution was cooled on an ice bath and 3-chlorobenzoyl chloride (0.3 mL, 2 mmol) added. After 6 hours, the mixture was diluted with EtOAc, washed with 1M hydrochloric acid solution (×3) and brine then dried over magnesium sulfate and concentrated to a solid. Purification by column chromatography (silica, 7:3 petrol)-EtOAc) afforded the title compound as a solid (300 mg, 39%); 1H NMR (400 MHz, CDCl3) 1.77 (9H, s), 7.52 (1H, t), 7.62 (1H, d), 7.90 (1H, d), 8.07 (1H, m), 8.32 (1H, d), 8.45 (1H, d), 9.22 (1H, brs), 9.32 (1H, s); MS (ES+) m/e=417.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH2:28][CH2:29]2)=[O:34])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using 1-(1-cyclopropylmethyl)-piperidine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a brown oil which was directly used in the next step without purification.
Reaction SMILES: C[C:2]1[C:3]([CH3:16])=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:17](O)(=O)C1C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:16][C:3]1[CH:2]=[CH:15][C:14]([CH3:17])=[CH:13][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: Cc1cccc(C(=O)c2ccccc2)c1C
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C)c(C(=O)c2ccccc2)c1

Procedure:
The dimethylbenzophenone fraction is contaminated with a small amount (0.05-0.1 lb/lb dimethylbenzophenones) of benzoic acid that co-distills with it. The benzoic acid is removed from the final product as described in Example 1. The washed dimethylbenzophenone product may or may not be given a final distillation in a 10 trays Oldershaw column to improve product color and purity as described in Example 1. Synthesis of dimethylbenzophenone from an isomeric mixture of xylenes will produce a mixture of six dimethylbenzo-phenone isomers. Synthesis from pure p-xylene will produce only 2,5-dimethylbenzophenone; pure m-xylene will produce 2,4-, 2,5-, and 2,6-dimethylbenzophenone; and pure o-xylene will produce 2,3- and 3,4-dimethylbenzophenone. Specific isomeric mixtures are produced by a provident choice of the composition of the initial xylene mixture.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].CCO[C:30]([CH3:32])=[O:31]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:10]4[CH2:9][CH2:8][N:6]([CH3:5])[C:30](=[O:31])[CH2:32]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Reactant: CCOC(C)=O
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 4 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 50.0 mg, 0.144 mmol), KF (42.6 mg, 0.719 mmol) and 1-methylperazine-2-one hydrochloride (67.0 mg, 0.431 mmol) were suspended in NMP (0.4 mL). The RM was stirred at 180° C. for 4 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.75 min (conditions 5), (tR 11.35 min (conditions 2), MH+=425.9, 1H-NMR in DMSO-d6: 8.07 (s, 1H); 7.80 (d, 1H); 7.52 (s, 1H); 7.36 (d, 1H); 7.05 (d, 1H); 4.85 (m, 1H); 4.01 (d, 1H); 3.95 (s, 3H); 3.78 (d, 1H); 3.62 (m, 2H); 3.27 (m, 2H); 2.81 (s, 3H); 1.79 (d, 3H)).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.Br.[Br:13][C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][N:16]2[CH:15]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Yield: 19.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2 g, 9.215 mmol) in 100 ml ethanol were added 5-bromo-thiazol-2-ylamine hydrobromide (2.396 g, 9.215 mmol) and ethyl-diisopropyl-amine (1.19 g, 9.215 mmol). The mixture was stirred under reflux for 8 h and evaporated. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 532 mg (20%) of the desired product. MS: M+H+=296.96.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([NH2:21])[CH2:18]2)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([NH:21][CH:19]1[CH2:20][N:17]([CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(NCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.134 cm3 of benzaldehyde is added, at room temperature under an argon atmosphere, to a solution of 369 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 15 cm3 of dichloromethane. The mixture is cooled to around 0° C., before gradually adding thereto 382 mg of sodium triacetoxyborohydride, and then 70 mm3 of acetic acid. After stirring for 16 hours at room temperature, the mixture is poured over 50 cm3 of a saturated aqueous sodium hydrogen carbonate solution and then extracted with twice 25 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (95/5 by volume)]. 0.29 g of N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amine is obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ ppm):2.71 (broad t, J=7 Hz,:2 H); 3.42 (mt:2 H); 3.49 (mt:1 H); 3.70 (s:2 H); 4.25 (s:1 H); from 7.20 to 7.40 (mt:13 H)].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][OH:27])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCCO
Product: CN(CCO)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(methylamino)ethanol were converted to yield 2-({4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol as colorless oil, MS: 374 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 42.5 °C

Procedure:
A mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 grams), methanol (80 ml), n-butyl amine (20 ml) and potassium carbonate (10.6 grams) was heated to 40-45° C. and stirred up to completion of the reaction. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH3:21])[C:15]([CH:22]=O)=[CH:14]2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:20]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:19][CH:18]=2)[CH:14]=[C:15]1[CH2:22][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:21]
Reactant: C1CCNCC1
Reactant: CCn1c(C=O)cc2cc(Oc3nc4ccccc4s3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCn1c(CN2CCCCC2)cc2cc(Oc3nc4ccccc4s3)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.8 %

Procedure:
To a suspension of 5-(benzothiazol-2-yloxy)-1-ethyl-1H-indole-2-carbaldehyde (100 mg, 0.3 mmol) in DCE (3 mL) was added piperidine (0.06 mL, 51 mg, 0.62 mmol), Na(OAc)3BH (131 mg, 0.62 mmol) and the reaction mixture was stirred (rt, 60 h). The reaction mixture was partitioned between saturated NaHCO3 (10 ml) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-8%) to provide the title compound as a yellow solid (82 mg, 68%). MS (ESI): mass calcd. for C23H25N3OS, 391.2; m/z found, 392.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.1, 1H), 7.59 (d, J=7.9, 1H), 7.49 (d, J=2.3, 1H), 7.39-7.29 (m, 2H), 7.23 (d, J=13.2, 1H), 7.12 (dd, J=8.8, 2.4, 1H), 6.35 (s, 1H), 4.36-4.21 (m, 2H), 3.56 (s, 2H), 2.49-2.25 (m, 4H), 1.54 (d, J=5.3, 4H), 1.51-1.32 (m, 5H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCc1ccccc1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2)c1
Yield: 78 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (293 mg, yield: 78.0%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:32][CH2:33][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].[K+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH:7]=1>CN(C)C=O.O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])[CH:7]=1
Reactant: [C-]#N
Reactant: ClCCCCCCc1cccnc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCCCc1cccnc1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A mixture of 4.0 g of potassium cyanide, 0.85 g of potassium iodide and 10.1 g of 6-(3-pyridyl)hexyl chloride in 100 ml of dimethylformamide was heated at 100° C. overnight. The reaction mixture was diluted with 200 ml of water and was extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and were evaporated. The residue was distilled to give 8.1 g (84%) of 3-pyridine heptanenitrile.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]([O:13][CH2:14][Cl:15])=[O:12].[CH2:16]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18].Cl>C1(C)C=CC=CC=1>[CH2:16]([N:20]([CH:21]([CH3:23])[CH3:22])[C:11](=[O:12])[O:13][CH2:14][Cl:15])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CNC(C)C
Reactant: O=C(Cl)OCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)CN(C(=O)OCCl)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Toluene (9 ml), 1.42 ml of N,N-diisopropylethylamine, and 0.56 ml of chloromethyl chloroformate were added in that order to 870 mg of N-isobutylisopropylamine, and the mixture was stirred at room temperature for 16 hr. 1 N hydrochloric acid (15 ml) was added thereto, followed by separation. The organic layer was washed with 15 ml of a 5% aqueous sodium hydrogencarbonate solution and 15 ml of 20% brine, was dried over anhydrous magnesium sulfate, and was filtered. The solvent was removed by distillation under the reduced pressure to give 1.23 g of chloromethyl N-isobutyl-N-isopropylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.[CH:20]1N=C[N:22](C(N2C=NC=C2)=O)[CH:21]=1.C(N)C>C1COCC1>[CH2:21]([NH:22][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[O:13][CH:14]([CH3:15])[CH3:16])=[O:19])[CH3:20]
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc2ccc(OC)cc2c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 mg, 0.77 mmol in 5 mL of THF is added N,N-carbonyldiimidazole (162 mg, 1.00 mmol). The solution is heated at reflux for 1 hour and cooled slightly. Ethylamine (0.44 mL of a 70% aqueous solution) is added and the reaction mixture is stirred at room temperature for 30 minutes, followed by partitioning between ethyl acetate, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (2:1) to provide N-ethyl-7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxamide in 70% yield; mp 78°-79° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)=[O:6]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 5 °C
Yield: 73 %

Procedure:
To a 22 L open-mouth round bottom flask fitted with a three-necked flange head, a mechanical stirrer, a nitrogen inlet and an outlet connected to a HCl scrubbing tower, is added 2,5-dichlorobenzoic chloride (4500 g, 21.5 mol) and phenyl ether (5489 g, 32.3 mol). The solution is cooled in ice to 5° C. under stirring, and aluminum chloride (3700 g, 27.8 mol) is added slowly, over a period of about 10 minutes. The temperature of the reaction mixture is about 35° C. after the addition. The mixture is then stirred for about 30 minutes and poured into about 20 gallons of ice water. The large reddish mass is dissolved by adding about 12 L of methylene chloride and stirring. The organic layer is separated and the aqueous layer is extracted with some methylene chloride. After methylene chloride is removed from the combined organic layer by distillation, the residue is recrystallized twice from cyclohexane (2×10 L), washed with cooled hexane, air dried, and then vacuum dried, to afford 5387 g monomer (73%). The mother liquor is kept for later recovery of remaining product.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:24][O:25][CH2:26][O:27][C:28]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:29]=1[C:30](OCOC)=[O:31]>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:7]1[C:2]([C:30](=[O:31])[C:29]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:28]=2[O:27][CH2:26][O:25][CH3:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ncccc1C1OCCO1
Reactant: COCOC(=O)c1cc(C)ccc1OCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C)cc1C(=O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (3.50 g) in THF (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.5 ml), which was stirred for 20 minutes. This reaction mixture was added, at the same temperature under argon atmosphere, to a solution of methoxymethyl 2-methoxymethoxy-5-methylbenzoate (3.66 g) in THF (50 ml). The mixture was stirred for 40 minutes, then for further one hour while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(1,3-dioxolan-2-yl)-2-(2-methoxymethoxy-5-methylbenzoyl)pyridine (2.06 g) (Compound E-14). The physical properties and spectrum data are shown in Table 16 and Table 19.
Reaction SMILES: C1(S(O[C@H:11]2[CH2:15][C@@H:14]([C:16](=[O:23])[NH:17][C:18]3([C:21]#[N:22])[CH2:20][CH2:19]3)[N:13]([C:24]([C:26]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:12]2)(=O)=O)C=CC=CC=1.[C:36]1([CH2:42][SH:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:42]([S:43][C@H:11]1[CH2:12][N:13]([C:24]([C:26]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:25])[C@H:14]([C:16]([NH:17][C:18]2([C:21]#[N:22])[CH2:19][CH2:20]2)=[O:23])[CH2:15]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Reactant: SCc1ccccc1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](SCc3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 457d) using (3S,5S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclopropylcarbamoyl)pyrrolidin-3-yl benzenesulfonate (example 457, step 3; 200 mg) and phenylmethanethiol (57 mg) to yield 109 mg (53%) of a white solid. MS (ESI): m/z=480.15 [M−H]+.