Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:16]1=[O:15])=[O:22]
Reactant: CC(c1ccccc1)N1CCC(C(=O)O)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccc1)N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid (0.101 g; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DFM (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxamide in two fractions (two sets of diastereoisomers) A 0.041 g (less polar fraction) and B 0.047 g (more polar fraction) (50% overall) as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl[C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:23][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCCC1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1ncc(Br)c1-c1cc(Nc2nc3ccccc3o2)ccc1OCCN1CCCCC1
Temperature: 60 °C
Yield: 18.4 %

Procedure:
To a mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine (0.034 g, 0.09 mmol) and 2-chlorobenzoxazole (0.016 g, 0.11 mmol) in isopropanol (1 mL), DIEA (0.031 mL, 0.18 mmol)) was added. The reaction mixture was heated at 60° C. for 4 days, concentrated then subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to afford Compound 199 (TFA salt) as an off-white solid in 18.4% yield. LCMS m/z (%)=496 (M+H 79Br, 90), 498 (M+H 81Br, 100). 1H NMR (400 MHz, Acetone-d6) δ: 11.80 (bs, 1H), 8.04 (dd, J=2.8, 9.0 Hz, 1H), 7.91 (d, J=2.8 Hz, 1H), 7.61 (s, 1H), 7.48-7.42 (m, 2H), 7.36 (d, J=9.0 Hz, 1H), 7.27 (dt, J=1.0, 7.6 Hz, 1H), 7.18 (dt, J=1.2, 7.8 Hz, 1H), 4.72-4.63 (m, 1H), 4.60-4.5 (m, 1H), 3.80 (s, 3H), 3.81-3.42 (m, 4H and water), 2.95-2.82 (m, 2H), 1.95-1.80 (m, 4H), 1.55-1.30 9 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][C:12]=2[CH3:14])[C:7](=[O:19])[C:6](=[N:20]O)[CH2:5]1)(=[O:3])[CH3:2].[C:22](NC1C=CC=C2C=1C(=O)C(=NO)CC2)(=[O:24])[CH3:23]>>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][C:12]=2[CH3:14])[C:7](=[O:19])[CH:6]([NH:20][C:22](=[O:24])[CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(=NO)CC2
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)C(=NO)CN2C(C)=O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CN2C(C)=O

Procedure:
The procedure of Example 1-(3) was followed by using 2.89 gm of the compound prepared in (2) above instead of 8-acetylamino-2-hydroxyimino-1-tetralone. The reaction product was post-treated to obtain 1.65 gm of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:43]3[CH:42]=[CH:41][C:40]([O:39][C:38]([F:37])([F:49])[F:50])=[CH:45][CH:44]=3)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCC(Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Yield: 34.2 %

Procedure:
3-{4-[1-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (isomer 1, 100 mg, 0.21 mmol), potassium carbonate (85 mg, 0.63 mmol), 4-triflouromethoxylphenyl boronic acid (86 mg, 0.42 mmol) and tetrakis-(triphenylphosphine)palladium (24 mg, 0.021 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, concentrated and acidified by 1 N HCl (0.6 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate, purified by reverse phase HPLC to give the title compound (40 mg). MS (ES): 526.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:15][C:14]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:13][C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10].[CH2:20]([O:22][CH:23]([N:25]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=2)=[N:28][N:27]=[N:26]1)[CH3:24])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29]4[N:25]([CH:23]([O:22][CH2:20][CH3:21])[CH3:24])[N:26]=[N:27][N:28]=4)=[CH:41][CH:40]=3)[C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10]
Reactant: CCCCc1nc2nc(C(OC)OC)c(Br)cc2[nH]1
Reactant: CCOC(C)n1nnnc1-c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cc(Br)c(C(OC)OC)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.3 %

Procedure:
0.61 g (1.86 mmole) of the compound obtained in step 8 was dissolved in 3 ml of DMF and thereto were added 0.79 g (2.05 mmole) of 2'-[1-(1-ethoxyethyl)-1H-tetrazol-5-yl]-biphenyl-4-ylmethylbromide and 0.51 g (3.72 mmole) of K2CO3. The resulting solution was stirred at room temperature for 5 hours and diluted with 50 ml of ethyl acetate. The resultant was washed with water (25 ml×3) and dried over Na2SO4, and then concentrated under reduced pressure and purified with column chromatography (hexane:ethyl acetate=1:1) to obtain 0.7 g of the title compound (yield 59%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH2:4][C@H:3]1[OH:10].S=[C:12]1[CH2:16][S:15][C:14](=[O:17])[NH:13]1>C(O)C>[F:8][C:6]1([F:9])[CH2:7][C@@H:2]([NH:1][C:12]2[CH2:16][S:15][C:14](=[O:17])[N:13]=2)[C@H:3]([OH:10])[CH2:4][CH2:5]1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@@H]1CC(F)(F)CC[C@H]1O
Solvent: CCO
Product: O=C1N=C(N[C@@H]2CC(F)(F)CC[C@H]2O)CS1
Yield: 56 %

Procedure:
To a solution of trans-2-amino-4,4-difluorocyclohexanol (1.08 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (950 mg), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (1000 mg).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@@H:27]3[CH2:31][CH2:30][N:29]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@@H]3CCNC3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@@H]3CCN(S(C)(=O)=O)C3)c12

Procedure:
3-(3-Chloro-phenyl)-1-((R)-1-methanesulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (29 mg) was prepared according to general procedure H from (R)-3-(3-chloro-phenyl)-7-methoxy-1-pyrrolidin-3-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (42 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 501 [M+1]+.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]([CH2:36][CH2:37][CH3:38])=[N:10][C:11]=2[CH:16]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(2-Chloro-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 2H), 7.48 (m, 3H), 7.30 (m, 3H), 7.21 (m, 2H), 6.81 (dd, 1H), 4.96 (s, 2H), 4.87 (s, 2H), 2.67 (t, 2H), 1.72 (m, 2H), 0.94 (t, 3H). MS calculated for C25H23FClN3O4S—H: 514, observed: 514.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[CH:40][CH:39]=4)=[CH:36][N:37]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[O:10])=[CH:45][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(C)CCCCBr
Product: CC(C)CCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCCC(=O)OC(C)(C)C)cc3)nc2)cc1

Procedure:
Prepared using General Procedure 12 from tert-butyl (S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate and 1-bromo-5-methyl hexane. LCMS-ESI (m/z) calculated for C44H56N4O5: 720.9. found 721.4 [M+H]+, tR=5.39 min. (Method 16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 78 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34–7.26 (m, 7H), 6.97 (d, 1H, J=7.6 Hz), 6.54 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=12.0 Hz), 2.54–2.48 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.00–1.95 (m, 4H), 1.84–1.60 (m, 10H); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: C(OC(N1C[CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)C1)=O)(C)(C)C.[N:33]1([C:39]([CH3:44])([CH3:43])[C:40]([NH2:42])=[O:41])CCNCC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:11][CH2:10][N:33]([C:39]([CH3:44])([CH3:43])[C:40]([NH2:42])=[O:41])[CH2:14][CH2:13]3)=[N:32][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
The title compounds was prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2-piperazin-1-yl-isobutyramide in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as an off-white solid (71 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Br:18]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:18][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCCCC(=O)c1ccc(Cl)s1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 118.8 %

Procedure:
Ethyl 6-(5-chloro-2-thienyl)-6-oxohexanoate (50.0 g) was dissolved in methylene chloride (150 ml), to which was added dropwise bromine (24.5 g) with stirring at room temperature. The mixture was stirred at room temperature for 1 hour, a 10% aqueous solution of sodium sulfite was then carefully added until disappearance of the red color of bromine, which was extracted with diethyl ether (200 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(5-chloro-2-thienyl)-6-oxohexanoate as an oil (64.4 g, >99%).
Reaction SMILES: C(N(C[CH2:11][C:12]1[C:13]([C:44](O)=[O:45])=[C:14]([N:29]([CH2:35][C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:30](OCC)=[O:31])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)C)C1C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][N:49]=1>>[CH2:35]([N:29]([CH2:11][C:12]1[C:13]2[C:44](=[O:45])[N:47]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][N:49]=3)[C:30](=[O:31])[N:29]([CH2:35][C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])[C:14]=2[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)[CH3:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CCN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(F)cn2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 63.1 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminoethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine (3.51 g, 31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(5-fluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (3.39 g, 32%) as white solids. The similar reaction as described in Reference Example 18 by using the compound (1.0 g, 1.46 mmol) gave the title compound (560 mg, 64%) as white solids.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][NH2:24].C([BH3-])#N.[Na+].Cl>CO.O>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:24][CH2:23][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NCCc1cccs1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cccc2c1CCC(NCCc1cccs1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.03 g of (0.01 mol) of 5-acetylamino-2-tetralone, 3.2 g (0.02 mol) of 2-(2-thienyl)-ethyl-aminehydrochloride and 0.75 g (0.012 mol) of sodium cyanoborohydride are dissolved in 30 ml of methanol and stirred for 24 hours at ambient temperature. The mixture is then acidified by the dropwise addition of conc. hydrochloric acid with stirring and cooling with ice. After 10 minutes, 100 ml of water is added whilst stirring continues and then a total of 4.0 g of anhydrous soda is added in batches. Then extraction is carried out with 50 ml of methylene chloride and twice with 25 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and after separation of the drying agent, concentrated by evaporation in a rotary evaporator, finally at 90° C. and under a complete water-jet vacuum. The residue is dissolved with 5 ml of methanol and 4.0 ml of 2.5 N ethanolic hydrochloric acid and the solution is mixed with diethylether until turbidity is just beginning. After standing for a period of about 12 hours at 5° C. the title compound is suction filtered, washed with ethanol/ether and dried at 80° C. until the weight remains constant. Yield: 3.1 g (88.3% of theory), melting point 276° C. (unchanged after recrystallisation from methanol/ether).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]2[NH:9][C:10](=[O:32])[C:11]3([CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[CH2:15][C:14](=[O:24])[N:13]([CH2:25][C:26](F)=[O:27])[CH:12]3[C:29]([CH3:31])=[CH2:30])[C:6]2=[CH:5][CH:4]=1>CO>[NH2:1][C:26]([CH2:25][N:13]1[C:14](=[O:24])[CH2:15][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:11]2([C:6]3[C:7](=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)[NH:9][C:10]2=[O:32])[CH:12]1[C:29]([CH3:31])=[CH2:30])=[O:27]
Reactant: N
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CO
Product: C=C(C)C1N(CC(N)=O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a solution of ammonia (2 M, 10 mL) in methanol was added racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.39 mmol) prepared in example 116d. The reaction mixture was stirred at room temperature for overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was separated, combined and concentrated. The residue was purified with chromatography (MeOH:EtOAc=5:95) to give racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 70 mg, 38.9%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35]Cl)[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH3:32]
Reactant: CCN(CC)C(=O)CCl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with N,N-diethylchloro acetamide and cesium carbonate in N,N-dimethylacetamide for 1 day at r.t., for 18 h at 50° C. and for 6 h at 100° C. to give N,N-diethyl-2-[[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetamide as a light yellow oil. MS: 588.8 ([M+NH4]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[Br:13]Br>C(O)(=O)C>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: CC(=O)O
Product: COc1cc(C=O)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
3,5-dimethoxybenzaldehyde (12.6 g, 76 mmol) was dissolved in acetic acid (350 mL). The resulting colourless solution was cooled to 0° C. A solution of bromine (3.9 mL) in ethanoic acid (50 mL) was added dropwise over 1 h. Once the addition was complete the ice bath was removed and the resulting pale green solution was stirred overnight at room temperature. Cold water was added to the solution. The resulting white solid was collected by vacuum filteration and rinsed with water. The solid was then redissolved in EtOAc and adsorbed on silica gel. The product was purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 1 (12.5 g, 66%) as a white solid. m/z=345.98 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.43 (1H, s, CHO), 7.06 (1H, s, ArH), 6.73 (1H, s, ArH), 3.93 (3H, s, CH3O), 3.86 (3H, s, CH3O). 13C NMR (500 MHz, CDCl3): δ: 192.09 (CHO), 159.92 (C-5), 157.02 (C-3), 134.67 (C-1), 109.12 (C-2), 105.83, 103.37 (C-4 & C-6), 56.60 (OMe), 55.82 (OMe).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].O>CN(C=O)C>[CH2:4]([NH:16][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17])[CH2:5][CH:6]([CH3:14])[CH3:7]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCNCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Anhydrous isopentylamine was bubbled into anhydrous DMF (200 mL) at 0° C. for 15 min. A solution of t-butyl 4-bromomethyl-3-nitrobenzoate (5.0 g, 15.8 mmol) (Int. J. Peptide. Res., 36, 31 (1990)) in DMF (10 mL) was added dropwise to the cold amine solution. The solution was stirred at 0° for 30 min and poured into water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, dried (sodium sulfate) and concentrated to give a yellow-brown oil. The oil was purified by chromatography over silica gel to yield t-butyl 4-(isopentylamino)methyl-3-nitrobenzoate.