Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:9][C@H:10]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][C@@H:10]([NH:9][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[S:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)N=C=S
Reactant: CCOC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Temperature: 20 °C
Reaction time: 48 h

Procedure:
7.5 cm3 of tert-butyl isothiocyanate are added to a solution of 13 g of ethyl (2R)-2-amino-5-[(benzyloxy)carbonyl]amino-pentanoate hydrochloride in 200 cm3 of ethanol, and the mixture is then stirred at a temperature in the region of 20° C. After 48 hours, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. to give 16 g of ethyl (2R)-5-{[(benzyloxy)carbonyl]amino}-2-(3-tert-butyl-thioureido)pentanoate in the form of a colorless oil [mass spectrum: EI m/z=409 M+ m/z=232 (C13H14NO3)+ m/z=142 (232-PhCH)+ m/z=91 (C7H7)+].
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6](CC1C=CC=CC=1)[CH2:7][CH2:8][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])#[N:2].Cl>C(O)C.[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])#[N:2]
Reactant: C[C@H](CCN(CCCC#N)Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@H](CCNCCCC#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.7 %

Procedure:
21 g (60.8.10-3 mol) of [3-[(3-cyanopropyl)(phenylmethyl)amino]-1-(R)-methylpropyl]carbamic acid, 1,1-dimethylethyl ester are dissolved in 400 ml of ethanol, and 0.25 ml of 10M hydrochloric acid is then added, followed by 1.2 g of 5% palladium on charcoal. The mixture is stirred under a hydrogen atmosphere at room temperature and at atmospheric pressure. After a reaction time of 24 hours, the catalyst is filtered off and the filtrate is then concentrated under reduced pressure. The residue is purified by chromatography on silica gel using an ethyl acetate/ethanol/aqueous ammonia mixture (6/3/0.1 v/v) as the eluent to give 6 g of the expected product in the form of an oil (yield=34%).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH2:24][CH2:23]2)[CH2:18][CH2:19]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](CN1CCC(OCC2CC2)CC1)CN1C(=O)COc2ccccc21
Reaction time: 72 h
Yield: 64.2 %

Procedure:
A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.199 g, 0.6 mmol), 4-cyclopropylmethoxypiperidine (0.093 g, 0.6 mmol), and K2CO3 (0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiO2; EtOAc) to give the title compound (0.138 g, 64%). 1H NMR (CDCl3) δ 6.99-6.97 (m, 1H), 6.85-6.79 (m, 3H), 4.47-4.35 (m, 2H), 3.85-3.74 (m, 2H), 3.14-3.08 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.64-2.61 (m, 1H), 2.49-2.46 (m, 1H), 2.10-2.04 (m, 2H), 2.00-1.68 (m, 6H), 1.47-1.38 (m, 2H), 0.90-0.84 (m, 1H), 0.71 (d, J=6.6 Hz, 3H), 0.37-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) δ 164.6, 145.4, 128.5, 123.4, 122.4, 116.9, 115.3, 75.0, 72.5, 67.5, 63.3, 52.6, 51.6, 45.0, 31.6, 31.5, 29.1, 16.7, 10.9, 2.9.
Reaction SMILES: [CH3:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[F:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([O:8][CH3:18])=[O:7]
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(C)cc1F

Procedure:
To a suspension of 4-methyl-2,5-difluorobenzoic acid (comm, 52 g, 0.3 mol) in methanol (1.0 L) was added concentrated sulphuric acid (3 mL) with stirring and the reaction heated to reflux under nitrogen for 18 hours. The reaction was quenched with aqueous sodium bicarbonate solution (10%, 150 mL), concentrated in vacuo and the resulting residue partitioned between EtOAc (800 mL) and water (400 mL). The organic layer was washed with water (250 mL) and brine (100 mL), dried with sodium sulphate and concentrated in vacuo to yield the title compound as a clear oil that solidified on standing (54.7 g, 98%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BrH:10].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: Br
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of 3-acetyl pyridine (2.71 ml, 24.74 mmol) in acetic acid (7.5 ml) was added 33% hydrobromic acid in acetic acid (7.5 ml) and then pyridinium tribromide (8.70 g, 27.21 mmol). The reaction mixture was stirred at room temperature for 12 hr to give a solid. The solid was filtered, washed with acetic acid and hexane and then dried under vacuum to give 2-bromo-1-pyridin-3-yl-ethanone 3.61 g (52%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][CH:9]([CH3:41])[CH2:10][C:11]1([C:38]([CH3:40])=[CH2:39])[CH2:16][CH:15]([CH2:17][O:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:14][C:12]1=[O:13]>C(Cl)Cl>[CH3:8][CH:9]([CH3:41])[CH2:10][C:11]1([C:38]([CH3:40])=[CH2:39])[CH2:16][CH:15]([CH2:17][OH:18])[O:14][C:12]1=[O:13]
Reactant: C=C(C)C1(CC(C)C)CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)C1(CC(C)C)CC(CO)OC1=O
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 70 %

Procedure:
TFA (15.0 mL) is added to a solution of [S-(R*,R*)]-α-(2-methylpropyl)-α-(propen-2-yl)-γ-trityloxymethyl-γ-butyrolactone (2.09 g, 4.60 mmol) and CH2Cl2 (30.0 mL) at 0° C. The solution is stirred for 75 minutes at 0° C. and is concentrated. Aqueous workup (CH2Cl2, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) provides 684 mg (70%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: CCNc1ccncc1[N+](=O)[O-]

Procedure:
In a manner similar to example 31, the title compound was prepared from 4-chloro-3-nitropyridine, prepared according to published procedure [J. Med. Chem. 1996, 39, 487–493], and ethylamine. 1H-NMR (CDCl3): δ 9.22 (1H, s), 8.30 (1H, d), 8.10 (1H, br s), 6.71 (1H, d), 3.40 (2H, m), 1.39 (3H, t).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N+:28]([O-])=O)[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)C>C1COCC1.Cl.[Zn]>[NH2:28][C:13]1[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]=12
Reactant: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
Zinc (414 mg, 0.006 mol) was added to a stirred solution of 1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (500 mg, 0.001 mol) in THF (50 mL) and concentrated HCl (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 400 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Reactant: NCCc1ccccc1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[C:18](O)=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][C:18](=[O:19])[C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[N:9]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Product: O=c1[nH]c2ccc(Br)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-bromo-2-nitroaniline and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-bromo-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]([C:42]([NH:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:43])[CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[O:25])[NH:16]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:58]>O1CCOCC1>[ClH:58].[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]([C:42]([NH:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])=[O:43])[CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[O:25])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 122A from 70 mg (0.09 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl-N5-[(benzyloxy)carbonyl]-N-(2-{[(benzyloxy)carbonyl]amino}ethyl)-L-ornithinamide (Example 123A) in 0.68 ml of a 4M solution of hydrogen chloride in dioxane.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N+:13]([CH3:16])([O-:15])=[O:14].C[O-].[Na+]>CO>[OH:1][C:2]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred and cooled mixture of ethyl 4-oxo-1-piperidinecarboxylate (85.5 g), nitromethane (33.6 g) in methanol (240 ml), sodium methoxide (10 g) is added dropwise. Upon completion, stirring is continued for 2 hours at about 10° C. and further overnight at room temperature. The reaction mixture is evaporated at room temperature, crushed ice is added to the oily residue and the whole is acidified with acetic acid. The product is extracted with trichloromethane, the extract is dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and dried, yielding 73 g of ethyl 4-hydroxy-4-(nitromethyl)-1-piperidinecarboxylate (interm. 5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([O-])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:15][CH2:16]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)[O-])C1CC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCO)C1CC1

Procedure:
This compound was prepared from N-tert-butoxycarbonyl-3-cyclopropylamino-propanoate (5a, 2.06 g, 8.0 mmol) using the procedure described in Example 2b. Yield: 1.22 g (71%). ESI-MS: 216.2 (M+H)+, 160.2 (M+H—C4H8)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.21.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23](OC(C)(C)C)=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:30][C:31]1[CH:32]=[N:33]C(Cl)=[N:35][CH:36]=1.CCN(C(C)C)C(C)C>CCO>[Br:30][C:31]1[CH:36]=[N:35][C:23]([N:19]2[CH2:20][CH2:21][O:22][C@H:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:33][CH:32]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(C(=O)OC(C)(C)C)CCO4)c3n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reaction time: 9 h
Yield: 74.8 %

Procedure:
(S)-tert-butyl 2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine-4-carboxylate (16.4 g, 54.69 mmol) was dissolved in EtOH (500 ml), and 5-bromo-2-chloropyrimidine (12.7 g, 65.62 mmol) and DIPEA (47.6 g, 273.45 mmol) were added, followed by 50° C. for 9 hours. After the completion of the reaction, the reaction mixture was recrystallized with EtOH to give (S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (18.7 g, 75%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (113 mg, 156 μl, 1.12 mmol) and methanesulfonyl chloride (42.8 mg, 29 μl, 374 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (96 mg, 95%), MS (ISP) m/z=407.4 [(M+H)+], mp 152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Product: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:8]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(O)CNCc2ccccc2)cc1
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(C(O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Alternatively, to a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanol (1.20 g, 4.66 mmol, see Preparation 61) and 3-methoxybenzaldehyde (0.700 g, 5.13 mmol) in 1,2 DCE (25 ml) was added NaB(OAc)3H. The mixture was stirred at RT overnight. The reaction mixture was poured into sat. NaHCO3 (30 ml) and extracted with CH2Cl2 (3×50 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (Biotage 15% EtOAc/hexanes) to give the title product (1.72 g, 4.56 mmol, 98% yield).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([S:18][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:16][CH:17]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCCC1>[C:23]([O:22][C:20](=[O:21])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([CH2:12][CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=2)[N:14]=1)([CH3:28])[CH3:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)O)cc2)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)benzoic acid methyl ester (7.0 g) obtained in Example 60-1 was dissolved in methanol (50 mL) and tetrahydrofuran (30 mL), 1 mol/L aqueous sodium hydroxide solution (24 ml) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.8 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](=[S:14])[NH2:13])=[C:5]2[N:4]=[N:3]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=O>CC#N>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:13]=[C:12]([C:11]3[N:10]=[CH:9][N:6]4[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[N:4][C:5]=34)[S:14][CH:16]=2)=[CH:20][CH:21]=1
Reactant: Cn1nnc2c(C(N)=S)ncn2c1=O
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC#N
Product: Cn1nnc2c(-c3nc(-c4ccc(Br)cc4)cs3)ncn2c1=O
Yield: 81 %

Procedure:
3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.48 mmol) and 2,4′-dibromoacetophenone (0.48 mmol) were stirred in MeCN overnight at room temperature. A slight yellow solid persisted which was filtered off before the remaining mixture was purified by preparative thin layer chromatography, eluting with 10% MeCN/DCM, to give the title compound. Yield=81%. δH (DMSO-d6): 8.92 (1H, s), 8.39 (1H, s), 8.04 (2H, d, J=8.8), 7. (2H, d, J=8.8), 3.89 (3H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[O:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:24][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][NH:21][C:20]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (82 mg, 0.241 mmol) in dichloromethane (4 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 241.0 (M+1)
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:29]([NH:33][C:25](=[O:26])[CH2:24][CH2:23][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:28])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 8 h

Procedure:
100 mg (0.268 mmol) of 4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoic acid, 23.5 mg (0.321 mmol) of t-butylamine, 3 mg (0.03 mmol) of 4-dimethylaminopyridine and 77.1 mg (0.402 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 1 ml of dichloromethane. 35.2 mg (0.348 mmol) of triethylamine was added to the obtained solution, and they were stirred overnight. The obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=2:1 to 4:6) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:31][C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=O)[O:27]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 57.5 %

Procedure:
Prepared from [2-amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G34) (163 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (126 mg, 0.55 mmol) according to the general procedure K. Obtained as a brown solid (143 mg).