Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.017 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.018 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of piperidine (1.6 g, 0.019 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction was concentrated in vacuo and the residue triturated in water (100 ml) and the mix was filtered. The filter cake was recrystallized from isopropyl alcohol-isopropyl ether to give 3.4 g (56%) of off-white flakes, mp 149°-150° C.
Reaction SMILES: C1C=C(C2SC(C3SC=CC=3)=CC=2)SC=1.ClS([N:20]=[C:21]=O)(=O)=O.[C:23]([C:25]1[S:29][C:28]([C:30]2[S:31][C:32]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[CH:33][CH:34]=2)=[CH:27][CH:26]=1)#[N:24]>C(Cl)Cl>[C:23]([C:25]1[S:29][C:28]([C:30]2[S:31][C:32]([C:35]3[S:36][C:37]([C:21]#[N:20])=[CH:38][CH:39]=3)=[CH:33][CH:34]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: c1csc(-c2ccc(-c3cccs3)s2)c1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)s3)s2)s1

Procedure:
α-Terthienyl (2.46 g, 0.01 m) was treated with two equivalents of chlorosulfonyl isocyanate (0.02 m) in methylene chloride as described in the preparation of 5-cyano-2,2':5',2"-terthienyl. Work-up as in that procedure gave crude product (2.4 g), m.p. 165°-170° C., contracting around 140° C. m/z 298(m+);
Reaction SMILES: O.[C:2]([O:5][C:6]1[CH:7]=[C:8]([O:16][C:17](=[O:19])[CH3:18])[CH:9]=[C:10]([O:12][C:13](=O)[CH3:14])[CH:11]=1)(=[O:4])[CH3:3].[H-].[Na+].C(Cl)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1.Cl>CN(C=O)C>[C:17]([O:16][C:8]1[CH:7]=[C:6]([O:5][C:2](=[O:4])[CH3:3])[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:9]=1)(=[O:19])[CH3:18]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(OCc2ccccc2)cc(OC(C)=O)c1
Reaction time: 16 h

Procedure:
Water (4.3 ml, 236 mmol) in DMF (20 ml) was added drop wise at room temperature with stirring to a mixture of acetic acid 3,5-diacetoxy-phenyl ester (refer Kawamoto. H. et. al. Synth. Commun. M, 531, 1996) (35 g, 139 mmol), NaH (5.66 g, 236 mmol) and benzyl chloride (19.16 ml, 166 mmol) in dry DMF (300 ml). The reaction mixture was stirred overnight (˜16 h), poured into chilled dil. aqueous HCl and extracted with CH2Cl2 to obtain the crude title compound which was purified using flash chromatography (silica ge, 20-50% CH2Cl2 in PE 60-80° C.). Yield, 12.5 g (30%), white solid; mp: 129-30° C.; MS (EI): 300 (M+), 258, 216, 91 (100%); analysis: C17H16O5 requires: C, 67.99; H, 5.37 found: C, 67.50; H, 5.40%.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11]([N:5]1[CH2:6][CH2:7][C:8](=[O:9])[CH:3]([CH3:2])[CH2:4]1)=[O:12]
Reactant: COC(=O)Cl
Reactant: CC1CNCCC1=O
Agent: Cl
Product: COC(=O)N1CCC(=O)C(C)C1

Procedure:
Racemic 3-methyl-4-oxo-piperidine-1-carboxylic acid methyl ester was prepared in the same manner from racemic 3-methyl-piperidin-4-one hydrochloride and methyl chloroformate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1ccc(Cl)cc1N
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc(Cl)cc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-5-chloroaniline to yield 2-[(2-methoxy-5-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][C@H:12]3[C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
A solution of 3.30 g (0.0098 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.30 g (0.0147 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 24 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark viscous residue was dissolved in 60 ml of THF, treated with 11.9 ml (0.0865 mol) of dipropylamine and stirred at room temperature for 24 hrs. The suspension obtained was filtered and the solution was completely freed from the solvents, the residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the residue was chromatographed over silica gel with dichloromethane/methanol 98:2 as the eluent. There were obtained 1.19 g (28%) of (S)-8-chloro-1-(5-dipropylaminomethyl-oxazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as yellow crystals; m.p. 148-151° (dec.) and [α]D20 =-101.7° (MeOH, c=1%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:46]([NH:48][CH3:49])=[O:47])[N:8]([C:32]4[CH:37]=[CH:36][C:35]([NH:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)=[CH:34][CH:33]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl>>[NH2:21][CH2:20][CH2:19][CH2:18][N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:12]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]2[C:10]([CH:11]=1)=[N:9][N:8]([C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:36][CH:37]=1)[C:7]=2[C:46]([NH:48][CH3:49])=[O:47]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCN)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of compound (iii) (10 mg crude, 0.02 mmol) and POCl3 (0.5 mL) was stirred at 130° C. for 3 h. The mixture was concentrated under pressure to give 3-[[2-(4-bromophenyl)-5-cyclopropyl-3-(methylcarbamoyl)indazol-6-yl]methylsulfonyl-amino]propane-1-sulfonyl chloride (iv) which was used directly without purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:7]2[N:8]([C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:7]2[N:8]([C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2c(C)c(C)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nn2c(C)c(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 40 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5,6-dimethyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step B) with trimethyltin azide according to the procedure of Example 1, Step G, furnished a 40% yield of the title compound as a light tan solid, mp 138°-141° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: C[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][C:8]([C:12]([OH:14])=O)=[N:9]2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:37]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([CH:50]([NH2:60])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:44][CH2:43]1)=[O:41])[CH3:38]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH2:37]([O:39][C:40]([N:42]1[CH2:43][CH2:44][N:45]([C:48]([CH:50]([NH:60][C:12]([C:8]2[CH:7]=[C:6]([OH:15])[C:5]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:9]=2)=[O:14])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:46][CH2:47]1)=[O:41])[CH3:38]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of 7-methyl-4-hydroxy-2-carboxyquinoline (0.81 g, 4 mmol) in methylene chloride:DMF (4:1, 25 mL) was added 1-hydoxybenzotriazole (HOBT) (0.64 g, 4.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.09 g, 4.8 mmol) and the reaction mixture was stirred for 10 minutes. A solution of 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (1.37 g, 4 mmol) in methylene chloride (10 mL) was added to the reaction mixture and the resulting mixture was stirred at ambient temperature for 6 hours. The solvent was evaporated in vacuo and the resulting residue was partitioned in ethyl acetate and water. The organic layers were combined and washed with water, brine and concentrated to afford an off-white foam, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline; (1.44 g, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].I[CH3:12]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([O:8][CH3:12])=[CH:6][CH:7]=1
Reactant: N#Cc1[nH]c(=O)ccc1Br
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(C#N)n1

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15/Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and iodomethane (1.2 eq.) in toluene (0.2 M) was stirred in the dark at room temperature overnight. The solvent was concentrated en vacuo, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 3-bromo-6-methoxypicolinonitrile.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10](=[O:49])[CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19](=[O:33])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:22][C:21]=2[OH:32])[CH:16]=[CH:15][C:14]=1[O:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]2[C:40]([O:43]COC)=[N:41][O:42][C:38]=2[CH:37]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.O.[OH-].[Na+]>O1CCOCC1.CO.C(OCC)(=O)C>[C:1]([O:7][CH2:8][O:9][C:10](=[O:49])[CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19](=[O:33])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:22][C:21]=2[OH:32])[CH:16]=[CH:15][C:14]=1[O:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]2[C:40]([OH:43])=[N:41][O:42][C:38]=2[CH:37]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: COCOc1noc2cc(COc3ccc(C(=O)c4ccc(OC5CCCC5)cc4O)cc3CCC(=O)OCOC(=O)C(C)(C)C)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)C(=O)OCOC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reaction time: 0.83 h
Yield: 58.7 %

Procedure:
1.02 g of {[3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl pivalate was dissolved in 8 mL of 1,4-dioxane and 8 mL of methanol, to which 6 mL of 6M hydrochloric acid was added at room temperature, and this mixture was stirred for 50 minutes at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 7 with an aqueous solution of sodium hydroxide, and then ethyl acetate was added to this mixture and the organic phase was separated therefrom. The remaining aqueous phase was extracted with ethyl acetate, and organic phases were combined together. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue, to which a mixture of hexane and ethyl acetate [3:1] was added, was filtered out to yield 0.56 g of [(3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoyl)oxy]methyl pivalate as white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[CH2:13]([C:17]([NH2:19])=[O:18])[C:14]#[C:15]C>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[C:14]([CH3:15])=[C:13]([C:17]([NH2:19])=[O:18])[N:7]=[N:6]1
Reactant: CC#CCC(N)=O
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)nnn1Cc1c(F)cccc1F

Procedure:
16.9 g (0.1 mole) of 2,6-difluorobenzyl azide and 8.3 g (0.1 mole) of but-2-ynecarboxamide are heated in 20 ml of dioxane for 16 hours to 100° C. After removing the dioxane by evaporation, the desired isomer is separated by column chromatography, to give 1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide with a melting point of 208°-210° C. (recrystallisation from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH2:10][N:9]=1.S(=O)(=O)(O)O.[N+:25]([O-])([O-:27])=[O:26].[K+].N>>[N+:25]([C:16]1[CH:17]=[CH:18][C:13]2[NH:12][C:11](=[O:19])[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CN=C(c2ccccc2Cl)c2ccccc2N1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1

Procedure:
To a solution of 13.5 g. of 5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 60 ml. of concentrated sulfuric acid, a solution of 5.5 g. of potassium nitrate in 20 ml. concentrated sulfuric acid is added dropwise. The solution is then heated in a bath at 45-50° for 2 1/2 hours, cooled and poured on ice. After neutralizing with ammonia, the formed precipitate is filtered off and boiled with ethanol. A small amount of white insoluble material is then filtered off. The alcoholic solution on concentration yields crystals of 7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one (clonazepam) which, after recrystallization from dichloromethane, melt at 238-240°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][C:13]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)=[O:14]
Reactant: c1ccc2c(c1)CCC2
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1ccc2c(c1)CCC2
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a stirred solution of indane (300 grams) and 3-chloropropionoyl chloride (323 grams) in methylene chloride (2 L) at 0° C. was added aluminum chloride (376 grams) over a period of 3 hours. Once the addition was complete, the cooling bath was removed and the mixture was warmed to room temperature and stirred until hydrogen chloride evolution ceased. The reaction was quenched by pouring onto a mixture of 3.5 kg of ice and 700 mL of concentrated hydrochloric acid. The layers were separated, and the aqueous phase was extracted with methylene chloride. The combined methylene chloride layers were washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to afford 282 grams of a yellow solid, m.p. 63.5-65.1° C.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](F)=[CH:14][CH:13]=1>>[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)=[CH:14][CH:13]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: OC1CNCc2sccc21
Product: Brc1ccc(OC2CNCc3sccc32)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 5) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:28][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][C@@H:22]4[CH2:25][CH2:24][C@@H:23]4[O:26]C)[C:14]=3[C:13]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:8][CH:7]=1.B(Br)(Br)Br>ClCCl>[CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:28][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][C@H:22]4[CH2:25][CH2:24][C@H:23]4[OH:26])[C:14]=3[C:13]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:10][CH:11]=1
Reactant: CO[C@H]1CC[C@H]1CNc1ncnc2[nH]c(-c3ccc(OCCN(C)C)cc3)c(-c3ccccc3)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)CCOc1ccc(-c2[nH]c3ncnc(NC[C@H]4CC[C@H]4O)c3c2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 6.5 h

Procedure:
A solution of 34 mg (0.07 mmol) of trans/cis-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-(2-methoxy-cyclobutylmethyl)-amine (Example 35, Step B) in 5 ml dichloromethane was cooled to −78° C. and treated with 80 μl (0.08 mmol) of 1 M solution of BBr3 in dichloromethane. The orange slurry was stirred at −78° C. for 6.5 h, and then was warmed to 0° C. for 20 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (5 ml) and stirred overnight. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic layers were dried over Na2SO4, filtered and purified by chromatography on silica gel (CH2Cl2:MeOH, 4:1 grading to CH2Cl2:MeOH, 1:1) to give the title compound. 1H-NMR (CD3OD) δ 0.91-0.99 (m, 1 H), 1.52-1.71 (m, 2 H), 2.03-2.10 (m, 1 H), 2.14-2.24 (m, 1 H), 2.39 (s, 6 H), 2.81 (t, J=4.0 Hz, 2 H), 3.50-3.57 (m, 1 H), 3.61-3.70 (m, 2 H), 4.10 (t, J=4.4 Hz, 2 H), 6.86 (d, J=6.8 Hz, 2 H), 7.27 (d, J=6.8 Hz, 2 H), 7.40 (d, J=6.0 Hz, 2 H), 7.42-7.51 (m, 3 H), 8.16 (s, 1 H). Mass Spectrum (ESI) m/e=458.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:29])[CH:5]=[C:6]([Cl:28])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([S:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:21]=[N:20]2)=[CH:15][CH:14]=1.[Cl:30][C:31](Cl)([Cl:35])[CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:28][C:6]1[CH:5]=[C:4]([O:29][CH2:33][CH:32]=[C:31]([Cl:35])[Cl:30])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:23]([S:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: CC(C)Sc1nnnn1-c1ccc(OCCCOc2c(Cl)cc(O)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1nnnn1-c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
900 mg of 3,5-dichloro-4-{3-[4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenoxy]-propoxy}-phenol, 720 mg of 1,1,1,3-tetrachloropropane, 691 mg of potassium carbonate and 10 mg of potassium iodide are stirred for 48 hours at 60° C. in 30 ml of acetone. The reaction mixture is filtered and the filtrate is concentrated. Purification over silica gel yields the title compound (compound 1.20).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:15]([CH2:17][C:18](=[C:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]([O:36][CH3:37])=[C:34]3[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]3[CH:38]3[CH2:40][CH2:39]3)=[CH:28][C:27]=2[F:45])[CH2:22][CH2:21]1)[Cl:19])C)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:19][C:18](=[C:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]([O:36][CH3:37])=[C:34]3[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]3[CH:38]3[CH2:40][CH2:39]3)=[CH:28][C:27]=2[F:45])[CH2:22][CH2:21]1)[CH2:17][NH:15][CH3:8]
Reactant: COc1c(N2CCC(=C(Cl)CN(C)Cc3ccccc3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(Cl)=C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.3 %

Procedure:
A solution of 161 (160 mg, 0.24 mmol) was dissolved in 1,2-dichloroethane (4 mL) and was treated with 1-chloroethyl chloroformate (0.8 mL, 7.3 mmol) under nitrogen. After 5 min, the reaction mixture was warmed to reflux temperature and the reaction mixture was allowed to stir for 3 h. The resulting mixture was allowed to cool to room temperature, and then it was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), adjusted to pH>7 by the addition of NaHCO3 and water at room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue purified by HPLC (reverse phase C-18 column, 35-90% acetonitrile/water containing 0.1% trifluoroacetic acid) to afford the trifluoroacetic acid salt of 72 (37 mg, 27%) as a yellow solid. MS 450 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.79 min; [M+H]+=420.50.
Reaction SMILES: [C:1]1([C@H:7]([NH:19][C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])[C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=1>>[N:25]12[CH2:26][CH2:27][CH:28]([CH2:29][CH2:30]1)[C@@H:23]([O:22][C:20](=[O:21])[NH:19][C@H:7]([C:8]1[CH:18]=[CH:17][CH:16]=[C:10]([O:11][CH2:12][C:13]([NH:31][C:32]3[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=3)=[O:15])[CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:24]2
Reactant: Nc1ccc(CO)cc1
Reactant: O=C(O)COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Product: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1ccc(CO)cc1

Procedure:
The title compound was prepared as described in Example 1 Step 10 with 2-(3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)acetic acid replacing 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl) phenoxy)methyl)benzoic acid and 4-aminobenzyl alcohol replacing 4-(2-hydroxyethoxy)-3-methylbenzaldehyde.