Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CCCc1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 88.9 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (11 g) and 4-propylaniline (10 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-propylphenyl)amine (17.6 g) was obtained. melting point: 74–76° C.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](CI)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6].Br.[OH:62][C:63]1[CH:64]=[C:65]2[C:69](=[CH:70][CH:71]=1)[CH2:68][NH:67][CH2:66]2.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:12]([N:67]3[CH2:66][C:65]4[C:69](=[CH:70][CH:71]=[C:63]([OH:62])[CH:64]=4)[CH2:68]3)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Oc1ccc2c(c1)CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3Cc4ccc(O)cc4C3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
2.4 g (2.53 mmol) of the powder obtained in Example 1 (B) was dissolved in 20 ml of N,N-dimethylformamide, and 0.77 g (3.56 mmol) of 5-hydroxyisoindoline hydrobromide and 0.6 ml (4.3 mmol) of triethylamine were added thereto. The mixture was stirred at room temperature for 1 hour. The dimethylformamide was distilled off under reduced pressure. The residue was subjected to silica gel flush column chromatography (ethyl acetate/n-hexane =3/1 to 1/0) to obtain 2.1 g (yield: 87%) of the above-identified compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C(=O)CC)[C@@H:16]([OH:31])[C@H:15]2[OH:32])=[C:7]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)=O.[CH2:48]([NH2:51])[CH2:49][NH2:50]>>[C:27]([O:26][C:24](=[O:25])[NH:19][C@H:17]1[CH2:18][C@@H:14]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][C:5]([C:3](=[O:2])[NH:50][CH2:49][CH2:48][NH2:51])=[N:6][C:7]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:15]([OH:32])[C@@H:16]1[OH:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: NCCN
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
A solution comprising 9-[(1R,2S,3R,4S)-4-(tert-butoxycarbonyl-propionyl-amino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (3.00 g, 4.66 mmol) in ethylenediamine (5 ml, 75 mmol) is heated at 90° C. for 1 hour. After cooling to room temperature, the ethylenediamine is removed in vacuo and purification by C-18 reverse phase column chromatography eluting with water (100%) followed by MeOH (100%) yields the title compound.
Reaction SMILES: N[C@H:2](C(OCC)=O)[CH2:3]CC(OCC)=O.CO.C([C:19]1[CH:40]=[CH:39][CH:38]=[CH:37][C:20]=1[C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])#C.[K+].[Br-]>C(Cl)Cl>[C:2]([C:39]1[CH:40]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=1)#[CH:3]
Reactant: C#Cc1ccccc1C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.55 g of 4-ethynylbenzoic acid (obtained from tert.-butyl 4-ethynylbenzoate in 84% yield by hydrolysis with trifluoroacetic acid) in 50 ml of anhydrous ether and 25 ml of anhydrous tetrahydrofuran is added 1.58 ml of triethylamine. This is followed by 1.00 g of phenyl N-phenylphosphoraminochloridate. After stirring the reaction mixture at room temperature under nitrogen for 0.5 hour, 0.90 g of diethyl L-glutamate is added in one portion. The mixture is allowed to stir for another 8 hrs. After a workup, the residue is subjected to column chromatography using a 1% methanol:methylene chloride mixture as the eluent. The major fraction isolated from the column contained 0.68 g (54%) of diethyl N-(ethynylbenzoyl)-L-glutamate as an oil which slowly solidified: NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11-2.60 (m, 4H), 3.23 (s, 1H), 4.09 (q, 2H, J=6.9 Hz), 4.27 (l, 2H, J=6.9 Hz), 4.80 (m, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4 Hz); IR (KBr) 3330, 3280, 2990, 1735, 1640, 1520, 1380, 1200, 1105, 1020, 855, and 770 cm- 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCBr
Reactant: OCCc1ccccn1
Product: BrCCCCOCCc1ccccn1
Yield: 61.1 %

Procedure:
From 2-pyridineethanol (5.0 g) and 1,4-dibromobutane (26.29 g), with a reaction time of 4 h. FCC eluting with ether-hexane (1:1) gave the title compound as a pale yellow oil (6.4 g), t.l.c. (ether-hexane 1:1) Rf 0.37.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[N:25]1([C:30]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:30]([N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)=[O:31])[CH:37]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: O=C(c1cccc(B(O)O)c1)N1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C(=O)N5CCCC5)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 9.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(pyrrolidine-1-carbonyl)phenylboronic acid (10 mg, 0.045 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(pyrrolidine-1-carbonyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.10 mg, 8%). 1H-NMR (MeOD): 1.82 (m, 2H), 1.91 (m, 2H), 2.04 (m, 1H), 2.21 (m, 1H), 3.02 (s, 3H), 3.39 (t, 2H), 3.52 (t, 2H), 5.82 (d, 1H), 6.95 (d, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.34 (m, 3H), 7.46 (m, 4H), 7.54 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[C:14]([Br:18])[NH:13]1.[F:19][C:20]([F:35])([C:31]([F:34])([F:33])[F:32])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[S:23](F)(=[O:25])=[O:24]>O1CCCC1.O>[CH3:11][N:12]1[C:16]([O:17][S:23]([C:22]([F:27])([F:28])[C:21]([F:29])([F:30])[C:20]([F:19])([F:35])[C:31]([F:34])([F:33])[F:32])(=[O:25])=[O:24])=[CH:15][C:14]([Br:18])=[N:13]1
Reactant: Cn1[nH]c(Br)cc1=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Br)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 0.70 mL, 0.70 mmol) was added at −78° C. under nitrogen to a stirred solution of 1-methyl-3-bromo-5-pyrazolone from Step 1 (0.10 g, mmol) in dry tetrahydrofuran (2 mL). After 10 min, nonafluorobutanesulfonyl fluoride (0.13 mL, 0.70 mmol) was added dropwise. The resulting gel was warmed to room temperature and stirred for 1 hour. The solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The extracts were dried (Na2SO4) and concentrated. Flash column chromatography on silica, eluting with 10% ethyl acetate—isohexane, gave 1-methyl-3-bromo-5-(nonafluorobutanesulfonyloxy)pyrazole (0.204 g, 79%) as a colourless oil. δ (1H, 500 MHz, CDCl3) 3.80 (3H, s), 6.19 (1H, s). Step 3: 1-methyl-3-bromo-5-(5-methylpyridin-2-yl)pyrazole
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:13]3)[CH2:4][CH2:3]1.CCN(CC)CC.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:12]2[N:11]=[C:10]3[N:14]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH:9]3[O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)=[CH:28][CH:27]=1)=[O:42]
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(N)cc4)nc32)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(NC(=O)C(C)(C)C)cc4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 16A) (100 mg, 0.258 mmole) in CH2Cl2 (2 mL) is added NEt3 (72 μL, 0.515 mmole) and pivaloylchloride (48 μL, 0.387 mmole). The reaction mixture is stirred at room temperature overnight. Solvent is removed under reduced pressure. AcOEt is added to the residue and the organic phase is washed with water and dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (100:0) to (90:10) to afford 2,2-dimethyl-N-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-propionamide melting at 120° C.
Reaction SMILES: C([Li])(C)(C)C.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.[CH:29](=[O:31])[CH3:30]>O1CCCC1>[OH:31][CH:29]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH3:30]
Reactant: CC=O
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.7M solution of t-butyllithium in hexane (8.03 ml, 13.65 mmol) was added dropwise, under nitrogen, to a stirred solution of 5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507, 1.0 g, 3.4 mmol) in dry tetrahydrofuran (35 ml) at about -70° C., ensuring that the temperature of the reaction mixture did not rise above -50° C. during the addition. The resulting mixture was allowed to warm to room temperature over a period of 1 hour, then cooled to about -70° C. and treated, dropwise, with a solution of acetaldehyde (0.15 g, 3.4 mmol) in dry tetrahydrofuran (5 ml). After being stirred for a further 0.5 hour at about -70° C., the reaction mixture was quenched with water and allowed to warm to room temperature. The bulk of the organic solvents was removed by evaporation under reduced pressure and the remaining mixture partitioned between ethyl acetate and 10% aqueous ammonium chloride solution. The organic phase was separated, combined with two further ethyl acetate extracts of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure to give an oil which was purified by column chromatography on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (1:20:79), to provide the title compound which was employed in the following Example without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14]C(=O)C(C)(C)C)[CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCc2cccc(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCc2cccc(Cl)c2)n1

Procedure:
This material was prepared in analogy to example 86 step B] from N-[6-(3-chloro-benzyloxymethyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (0.75 g) and 3M aqueous NaOH (4.51 mL) as a brown liquid (0.56 g). MS (ESI): 249.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)CC>ClCCl>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Yield: 65.8 %

Procedure:
2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[Cl:10][CH2:11][CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:24][C:18]=3[C:17]([N+:29]([O-:31])=[O:30])=[CH:16][C:15]=2[N:14](C(=O)C(F)(F)F)[CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].CO>O>[Cl:10][CH2:11][CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([S:25]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:26])=[O:27])=[CH:24][C:18]=3[C:17]([N+:29]([O-:31])=[O:30])=[CH:16][C:15]=2[NH:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
t-Butyl carbazate (86 mg, 0.65 mmol) was added to a solution of 116 (107 mg, 0.23 mmol) in ThF (5 mL) and the mixture was stirred at room temperature for 16 h. Cs2CO3 (150 mg, 0.46 mmol) and MeOH (2 mL) were added and the mixture was stirred for a further 2 h. The mixture was diluted with water and extracted with CH2Cl2 (×2). The combined extracts were dried and evaporated and the residue was purified by chromatography, eluting with EtOAc/petroleum ether (1:4 then 2:3). The product was recrystallised from EtOAc/petroleum ether to give tert-butyl 2-{[1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}hydrazinecarboxylate (119) (72 mg, 67%) as an orange crystalline solid: mp 179° C. (dec.); 1H NMR [(CD3)2SO] δ 9.60 (br s, 1H), 9.18 (v br s, 1H), 8.54 (d, J=1.4 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 7.74 (dd, J=8.9, 1.8 Hz, 1H), 6.74 (s, 1H), 4.29-4.22 (m, 1H), 3.94-3.85 (m, 2H), 3.80 (dd, J=11.0, 8.0 Hz, 1H), 3.74 (dd, J=10.5, 3.0 Hz, 1H), 1.10 (br s, 9H). HRMS (FAB) calcd. for C18H2135ClN4O6S (M+) m/z 456.0870, found 456.0877.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>O>[N+:12]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH2:1][CH3:2])[C:7]([OH:9])=[O:8])([O-:14])=[O:13]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Ethylbenzoic acid (12.0 g, 79.9 mmol) was added portionwise to fuming nitric acid (62 mL) with stirring at room temperature. Following the addition, the mixture was poured into water (500 mL), stirred, and extracted with ethyl acetate (300 mL). Saturated brine (150 mL) was added and the mixture shaken then separated. The organic solution was washed with brine then dried over magnesium sulfate. Filtration, removal of the solvent by rotovap under reduced pressure, and trituration of the residue in hexane afforded the product (13.3 g); pure after recrystallization from hexane/ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: Cc1csc2c(NC3CC3)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC2CC2)c2scc(C)c2n1
Yield: 84.8 %

Procedure:
In a sealed tube were heated 287 g (1.2 mmol) of 2-chloro-4-cyclopropylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 265 mg (yield: 84.9%) of the title compound.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>>[CH3:3][CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)CCCC(C)Br
Product: CC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
2-bromo-6-methyl-heptane was reacted with p-hydroxy-acetophenone to obtain p-[(1,5-dimethyl-hexyl)-oxy]-acetophenone (boiling point = 200°C/1.0 mmHg);
Reaction SMILES: C([C:3]12[CH:8]([C:9]([OH:11])=[O:10])[CH:7]1[CH2:6][CH2:5][C:4]2=[O:12])C.[OH-].[Na+]>>[O:12]=[C:4]1[CH2:5][CH2:6][CH:7]2[CH:3]1[CH:8]2[C:9]([OH:11])=[O:10]
Reactant: CCC12C(=O)CCC1C2C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CCC(=O)C21

Procedure:
(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid may be prepared by reacting carbethoxymethyl dimethylsulfonium bromide with 2-cyclopenten-1-one in the presence of a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene to afford ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate. This ester may then be reacted with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce an intermediate hydantoin, (the Bucherer-Bergs reaction), which is then hydrolysed using sodium hydroxide, to afford a diastereomeric mixture of diethyl 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. The desired diastereomer may be obtained by crystallization with oxalic acid. This diastereomer may then be resolved by forming a crystalline salt with (+)-di-p-toluoyl-D-tartaric acid and recovering (-)-diethyl 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate- Hydrolysis of this diester using aqueous sodium hydroxide gives (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Alternatively, the ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid may be hydrolysed using sodium hydroxide to give 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. This acid may then be resolved by forming a crystalline salt with (S)-1-phenylethylamine and recovering (+)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. This acid may then be converted into (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid by reaction with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce an intermediate hydantoin (the Bucherer-Bergs reaction) followed by hydrolysis of the hydantoin using sodium hydroxide. This procedure may also be modified by performing the resolution step on the hydantoin rather than on the 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. In this case, (R)-1-phenylethylamine has been found to be a suitable resolving agent.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([NH2:16])[C:4]=2[CH:3]=1.[C:17]1([CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([NH:16][C:29]([CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:30])[C:4]=2[CH:3]=1
Reactant: NC1c2ccccc2Sc2ccc(Cl)cc21
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Product: O=C(CCc1ccccc1)NCC(=O)NC1c2ccccc2Sc2ccc(Cl)cc21

Procedure:
Prepared in analogy to example 1.1 from rac-2-chloro-9H-thioxanthen-9-ylamine (CA [51065-24-8]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Br:15])[CH:12]=[C:13]([F:14])[C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[Br:15][C:11]1[CH:12]=[C:13]([F:14])[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2c(F)cc(Br)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(F)cc(Br)cc2s1
Yield: 88 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, 6-bromo-4-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (I-26b: 2.3 g, 7.85 mmol) in THF (25 mL) was hydrolyzed with LiOH (1.65 g, 39.38 mmol) and water (20 mL) to afford 1.9 g of the product (83% yield).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][N:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1ccc(-c2ccc([C@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Dimethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (80 mg, 0.180 mmol) in CH2Cl2 (0.32 mL) is added trifluoroacetic acid (0.32 mL). Reaction mixture allowed to warm to room temperature and stirred for 2 hours. The volatiles are removed under reduced pressure to obtain crude material purified by column chromatography eluting in 40% methanol in CH2Cl2 to afford the title compound (60 mg). LC-MS (m/z): [M+H]=304.1.