Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1[C:17]([CH3:22])=[N:18][O:19][C:20]=1[CH3:21].[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>CO>[CH3:22][C:17]1[C:16]([CH2:15][N:5]2[CH2:6][CH2:7][C:8](=[O:14])[N:9]([CH3:13])[C:10]3[C:4]2=[N:3][C:2]([NH:23][C:24]2[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[O:29])=[CH:26][C:25]=2[O:40][CH3:41])=[N:12][CH:11]=3)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1c(C)noc1C)CCC(=O)N2C
Temperature: 150 °C

Procedure:
9-chloro-6-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-3-one (Intermediate 156; 81 mg, 0.25 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 80 mg, 0.30 mmol) p-toluenesulphonic acid monohydrate acid (96 mg, 0.5 mmol) and isopropanol (4 mL) were combined in a 10 mL microwave reactor tube and heated in by microwave irradiation at 150° C. for 80 minutes. The sample was transferred to an SCX (20 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as an off white gum (61 mg, 45%).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH3:4].[CH2:5]=O.[CH:7](=[C:12]1/[C:13](=[O:17])[CH2:14][CH2:15][CH2:16]/1)\[CH2:8][CH2:9][CH2:10][CH3:11].C>Cl.C(O)C>[ClH:1].[CH3:2][N:3]([CH2:5][CH:14]1[CH2:15][CH2:16]/[C:12](=[CH:7]\[CH2:8][CH2:9][CH2:10][CH3:11])/[C:13]1=[O:17])[CH3:4]
Reactant: CCCC/C=C1\CCCC1=O
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCCC/C=C1\CCC(CN(C)C)C1=O
Reaction time: 8 h
Yield: 62.8 %

Procedure:
4.1 g of dimethylamine hydrochloride, 3.7 g of paraformaldehyde and 20 ml of ethanol were added with 5 drops of concentrated hydrochloric acid to 7.6 g of 2-(E)-pentylidene cyclopentanone. After refluxing for about 2 hours, the resulting solution was mixed with 2.2 g of paraformaldehyde and then refluxed for about 2 additional hours. The solution was treated with activated charcoal and filtered. The filtrate was allowed to stand overnight, filtered and washed with cold ether containing a small amount of absolute ethanol to give 7.7 g of 2-Dimethylaminomethyl-5-(E)-pentylidene cyclopentanone hydrochloride as colorless leaflets. The melting point of the product was determined to be 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=3)=[O:10])=[CH:12]2)[CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 4ww was prepared following the procedure described in Step 3 of Example using 45 mg (0.16 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one 3d, 8 mg (0.21 mmol) of 60% sodium hydride and 53 mg (0.21 mmol) of 2-bromo-6-bromomethyl-pyridine in 0.7 mL N,N-dimethylformamide and stirring the reaction mixture at rt for 2 h. The product was purified using reverse phase HPLC (mobile phase with a gradient 10-50% acetonitrile in 50 min). The HPLC fractions containing pure product were combined, evaporated under vacuum and neutralized using methanolic ammonia and purified by flash chromatography (using 30-100% ethyl acetate in hexane) to give 18 mg of a pale yellow solid: LC-MSD, m/z for C23H18BrN3O2 [M+H]+: 448.4, 450.4; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.1 min; 1H NMR (400 MHz, CDCl3): δ 2.35 (s, 3H), 2.5 (s, 3H), 5.5 (s, 2H), 7.0-7.1 (m, 1H), 7.3-7.35 (m, 1H), 7.35-7.4 (m, 1H), 7.4-7.6 (m, 4H), 7.6-7.7 (m, 1H), 8.4-8.45 (m, 1H), 8.5 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[C:36]([O:41][CH3:42])(=[O:40])[C:37]([CH3:39])=O>CCCCCC.CCOCC.C1C=CC=CC=1>[CH3:39][C:37](=[CH:2][CH2:3][CH:4]=[C:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:36]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)C(C)=O
Reactant: CCCCCC(C)=CCCBr
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCC(C)=CCC=C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.0 g. of 1-bromo-4-metyl-3-nonene and 6.35 g. of triphenylphosphine in 25 ml. of dry benzene is heated under reflux for 12 hrs., then the mixture is allowed to cool to 25°C. and 50 ml. of dry ether and 11 ml. of 15% n-butyl lithium in hexane are added. The resulting mixture is stirred for 2 hrs. at 25°C., giving a red solution, then 2.5 g. (2.15 ml.) of methyl pyruvate in 10 ml. of ether is added and the mixture is stirred at room temperature (about 25°C.) for 18 hrs. The solvents are then removed by evaporation under reduced pressure and the resulting residue is dissolved in methylene chloride and chromatographed over silica gel. Elution with 5,10 and 20% ethyl acetate in cyclohexane and evaporation of the eluate fractions gives a residue comprising methyl 2,6-dimethyl-2,5-undecadienoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:30])([F:18])[F:31])=[CH:25][CH:24]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 16.3 %

Procedure:
Example 14 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and [4-(trifluoromethyl)phenyl]acetic acid (0.041 g) to give thetitle compound (0.015 g).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=3[CH2:12][N:11](S(C)(=O)=O)[C@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:4]=[CH:3]1.NC1C=CC2CN([C:55]([O:57][C:58](C)([CH3:60])[CH3:59])=[O:56])C(CC3C=CC=CC=3)CN(CC3N=CNC=3)C=2C=1.C1(C)C=CC=CC=1.[Cl:71]C(OC(C)C)=O>CCOC(C)=O.CCCCCC>[ClH:71].[C:19]([C:17]1[CH:16]=[CH:15][C:14]2[N:8]([CH2:7][C:5]3[N:4]=[CH:3][NH:2][CH:6]=3)[CH2:9][C@@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:11]([C:55]([O:57][CH:58]([CH3:60])[CH3:59])=[O:56])[CH2:12][C:13]=2[CH:18]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2N(Cc2c[nH]cn2)CC1Cc1ccccc1
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)OC(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Yield: 42 %

Procedure:
Example 358 was prepared as a light yellow solid in 42% yield from Compound C of Example 248 by the following sequence: Compound E of Example 248, using a toluene solution of isopropyl chloroformate with chromatography using 40% hexane in EtOAc and with the free base carried on; Example 354.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:33][C:19]1[N:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[S:22][C:18]=1[CH2:17][S:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc(OCC(=O)O)c2c1OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
{8-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-5-yloxy}-acetic acid methyl ester dissolved in 5 ml THF and 1 ml water, was treated with lithium hydroxide monohydrate (327 mg, 7.8 mmol); stirring at room temperature for 1 hour. The reaction mixture was then acidified to about pH 3 with 2 N HCl. The reaction was then extracted into ethyl acetate (2×20 ml). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. Recrystalization from chloroform/hexanes afforded the title compound (750 mg, 96%) as a pale yellow solid. IR (thin film) cm−1: 1745; 400 MHz 1H NMR (DMSO-d6) δ 7.98 (d, 2H, J=8.0 Hz), 7.75 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=8.5 Hz), 6.27 (d, 1H, J=8.5 Hz), 4.60 (s, 2H), 4.18 (s, 2H), 4.11 (t, 2H, J=4.6 Hz), 2.56 (t, 2H, J=6.6 Hz), 2.15 (s, 3H), 1.83 (m, 2H).; MS m/z 496 (M+1). Anal. Calc'd for C23H20F3N1O4S2 0.3 CHCl3 C, 52.67; H, 3.85; N, 2.64; found: C, 52.49; H, 3.77; N, 2.54.
Reaction SMILES: [N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8])=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
8 g (17.4 mmol) of Boc-Pro-Gly-Pro-OBzl were dissolved in 100 ml of methanol, 0.5 ml of CH3COOH and palladium black were added, while stirring on a magnetic stirrer, and hydrogen was passed through for 2 hours. The solution was filtered, evaporated, evaporated 3 times with benzene and 2 times with ethyl acetate. Then, it was precipitated with ether hexane from acetone, and the precipitate formed in the flask was dried in a desiccator over P2O5/KOH and paraffin.
Reaction SMILES: Cl[CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[OH:15][C:9]1[CH:14]=[CH:13][C:12]([CH:2]2[NH:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: O=C1NC(=O)C(Cl)N1
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 70 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
1.34 g (10 mmol) of 5-chlorohydantoin and 1.88 g (20 mmol) of phenol were dissolved in 10 ml of dioxane. The solution was then heated to a temperature of 70° C. with stirring for 6 hours. The reaction system was then allowed to cool to room temperature. The reaction system was further cooled over an ice bath for 2 hours. The resulting crystal was recovered by filtration, washed thoroughly with water, and then air-dried to obtain 0.93 g (4.8 mmol; yield: 48%) of 5-(p-hydroxyphenyl)hydantoin in the form of white crystal. The crystal thus obtained exhibited a melting point of 262° to 264°0 C. (decomposition). The IR spectrum, NMR spectrum, and Rf value of thin layer chromatography showed a good conformance to that of a specimen which had been separately synthesized.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([NH:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[C:10](=[O:11])[N:12]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.2 %

Procedure:
To 61.29 g (270 mmol) of the material of Example I dissolved in 1300 ml of anhydrous N,N-dimethylformamide ("DMF") (Aldrich; Cat. No. 22, 70506), was added 28 ml (296 mmol) of acetic anhydride (Aldrich; Cat. No. 11,004-3), and the resulting mixture was stirred at room temperature for 20 hrs. DMF was removed under reduced pressure, and the resulting residue was treated with the excess of 100 ml dimethyl ether; 71.4 g (98% yield) of a crystalline product was obtained and collected by filtration, washed thoroughly with dimethyl ether, and dried over P2O5 for 3 hrs. This product had a melting point of 150°-170° C.; the published melting point for this product 154°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=O)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:20])[CH:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:37]([F:42])[CH:36]=1)[CH3:32]
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid ethyl ester (CAS Reg. No. 73792-12-8) in the presence of DMAP to give the title compound as colorless oil. MS: m/e=534.3 [M+H+].
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O1CCCC1.Cl.[NH2:24][C:25]1[C:26]([OH:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29]>C(Cl)Cl>[OH:34][C:26]1[C:25]([NH:24][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(=O)O)c1O)c1ccncc1
Yield: 76.5 %

Procedure:
A mixture of isonicotinic acid chloride hydrochloride (2.34 g, 13.2 mmol), triethylamine (1.83 ml, 13.2 mmol) and tetrahydrofuran (10 ml) was added dropwise to a mixture of methyl ester of 3-amino-2-hydroxybenzoic acid hydrochloride (2.0 g, 12.0 mmol), N,N′-dimethylaniline (3.04 ml, 24.0 mmol) and tetrahydrofuran (20 ml) with stirring under ice cooling, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was diluted with methylene chloride (200 ml), washed with water and brine in turn and then dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on amine silica gel (Chromatolex (trademark) NH) (n-hexane/ethyl acetate=4 and chloroform/ethyl acetate=1) to give methyl ester of 2-hydroxy-3-isonicotinoylaminobenzoic acid (2.37 g, 73%) as pale yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cl-:14].[NH4+]>CO.O.[Fe]>[ClH:14].[I:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1cc(I)c2[nH]ccc2c1
Agent: [Fe]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cl
Product: Nc1cc(I)c2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 120.8 %

Procedure:
A solution of 7-iodo-5-nitro-1H-indole III (20 g, 69.4 mmol) in methanol (650 mL) at 25° C. was treated with a solution of ammonium chloride (26.1 g, 485.8 mmol) in water (550 mL) and iron powder (13.6 g, 242.9 mmol). The mixture was heated to 100° C. under a nitrogen atmosphere for 5 h. The resulting mixture was filtered through a pad of celite and the celite pad washed with hot methanol. The filtrate was concentrated in vacuo and the residue was partitioned between methylene chloride and water and separated. The pH of the aqueous layer was adjusted to pH=10 with ammonium hydroxide and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to a volume of 250 mL. This solution was treated with a 4.0 M aqueous hydrochloric acid solution in dioxane and stirred at 25° C. for 2 h. The precipitate was collected by filtration and washed with methylene chloride and petroleum ether to afford 7-iodo-1H-indol-5-ylamine hydrochloride IV (24.7 g, quant.) as a gray solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.34 (broad s, 1H), 9.93 (broad s, 2H), 7.56 (d, J=1.46 Hz, 1H), 7.48 (t, J=2.74 Hz, 1H), 7.44 (d, J=1.83 Hz, 1H), 6.68 (dd, J1=1.83 Hz, J2=2.93 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:27](=[O:28])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:8][C:4]=2[CH:3]=1
Reactant: NCC1Cc2cc(Cl)c3ccccc3c2O1
Reactant: O=C(Cl)OCc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(Cl)c3ccccc3c2O1)OCc1ccccc1
Yield: 88.6 %

Procedure:
Treatment of (±)-1-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine (0.83 g, 3.07 mmol) with diisopropylethylamine (1.20 g, 9.28 mmol) followed by benzyl chloroformate (0.79 g, 4.60 mmol) generally according to the procedure described for Intermediate 7 provided 1.00 g (89%) of (±)-benzyl (5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methylcarbamate as a white solid. mp 117-119° C.; Anal. calcd. for C21H18ClNO3.0.5H2O: C, 66.93; H, 5.08; N, 3.72. Found: C, 66.81; H, 4.96; N, 3.67.
Reaction SMILES: ClC1CCC2C(=CC(OC)=CC=2)C1.C(OC(=O)C)C.[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH2:28][CH2:27][C:26]=1[Cl:37])[CH3:21].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.CO>[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[CH:27][C:26]=1[Cl:37])[CH3:21]
Reactant: CCOC(=O)CC1=C(Cl)CCc2ccc(OC)cc21
Agent: COc1ccc2c(c1)CC(Cl)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
A mixture of [2-Chloro-7-methoxy-3,4-dihydro-2H-naphthalen-(1 E/Z)-ylidene]-acetic acid ethyl ester and of (2-Chloro-7-methoxy-3,4-dihydro-naphthalen-1-yl)-acetic acid ethyl ester (26.82 g, 95.52 mmol) is dissolved under an atmosphere of argon in dioxane (280 ml). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ, 47.70 g, 210.16 mmol) is added, and the reaction mixture is refluxed for 2 h. TLC analysis indicates complete conversion of starting material. After cooling to RT, addition of MeOH renders the reaction mixture homogeneous. Silica gel (250 g) is added, and the solvent is removed by rotary evaporation. Purification by FCC (hexane/EtOAc 9:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.24 (t, J=8.8 Hz, 3H), 3.95 (s, 3H), 4.19 (q, J=8.8 Hz, 2H), 4.28 (s. 2H), 7.16-7.19 (m, 1H), 7.22 (s, 1H), 7.38 (d, J=10 Hz, 1H), 7.68 (d, J=10 Hz, 1H), 7.75 (d, J=10 Hz, 1H). ES+-MS: 279.2, 281.2 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]1[N:24]=[C:23]([NH:25][C@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1>O.C(O)CCC>[CH3:49][O:48][C:42]1[CH:43]=[CH:44][C:39]([CH3:38])=[CH:40][C:41]=1[C:15]1[N:24]=[C:23]([NH:25][C@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)nc3ccccc23)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Yield: 88 %

Procedure:
A mixture of toluene (1.8 mL), n-butanol (3 mL) and 2M Na2CO3 (3 mL) was degassed with a stream of nitrogen for 20 minutes. The mixture was transferred onto a degassed mixture of (S)-tert-butyl 3-(2-chloroquinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.300 g, 0.86 mmol), palladium tetrakistriphenyl phosphine (0.0718 g, 0.06 mmol) and 5-methyl-2-methoxyphenylboronic acid (0.143 g, 0.86 mmol) and the solution was heated at reflux. After 17 hours the reaction was cooled, diluted with water (20 mL), and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), and concentrated. Silica chromatography (6:1-1:1 petroleum ether/ethyl acetate) gave the title compound as a colourless solid (0.329 g, 99%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:4]21[O:8][CH2:7][CH2:6][O:5]2.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][C:4]21[O:5][CH2:6][CH2:7][O:8]2)(=[O:24])=[O:23]
Reactant: OCC1CC(CO)C2(C1)OCCO2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)C2(C1)OCCO2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6,8-Bis(hydroxymethyl)-1,4-dioxaspiro[4.4]nonane (8.18 g, 43.5 mmol) was dissolved in dichloromethane (200 ml) and chilled to 0° C. To the chilled solution was added 4-dimethylaminopyridine (0.53 g, 4.4 mmol) and distilled triethylamine (18.2 ml, 131 mmol). Then methanesulfonyl chloride (7.41 ml, 11.0 g, 95.7 mmol) was added drop-wise via syringe over 10 min and the reaction was allowed to come to ambient temperature and stir for 18 h under nitrogen. The reaction was quenched with saturated sodium bicarbonate (25 ml) and stirred for 30 min. After stirring, the layers were separated and the aqueous phase extracted with dichloromethane (2×50 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield a reddish brown oil (14.9, 99.4%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[CH3:27]I>CS(C)=O>[OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH3:27])=[S:25]
Reactant: C[C@@H]1N[C@@H](CO)Cc2c1[nH]c1ccccc21
Reactant: CI
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CSC(=S)N1[C@@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1C

Procedure:
In the same manner as described in Example 13 by using (1RS, 3SR)-trans-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (1.08 g), triethylamine (1.01 g), CS2 (760 mg), methyl iodide (1.42 g) and dimethylsulfoxide (10 ml), there is prepared the title compound (1.22 g, 79.7%) as colorless needles, m.p. 153°-156° C. (recrystallized from aqueous methanol). NMR (CDCl3, δ): 2.60 (d, J=7.0 Hz, 3H, C1 --CH3), 2.68 (s, 3H, CSSCH3), Mass m/e: 306 (M+), 258 (M+ --CH3SH).