Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[C:28]([CH:39]=[CH:40][CH:41]=4)[O:29][CH2:30]CCCCCCCS)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C=CC=1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:7][CH:8]=1.[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:41]=[CH:40][CH:39]=[C:28]([O:29][CH3:30])[CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: SCCCCCCCCOc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: COc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1

Procedure:
A colorless viscous matter of 8-[3-(3,6-diphenylcarbazole-9-yl)phenoxy]octane-1-thiol (C-4) (hereinafter referred to as carbazole derivative 6) represented by the chemical structure 12 is obtained in the same manner as in preparation of Carbazole Derivative 1 except that 3,6-diphenyl-9-(3-methoxyphenyl)carbazole is used instead of 3,6-bis(5-methylthiophene-2-yl)-9-(4-methoxyphenyl)carbazole (B-2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([CH2:18][CH3:19])([OH:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15]Br)=[CH:8][CH:7]=1.[CH2:23]([NH:26][CH2:27][CH2:28]C)[CH2:24]C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([CH2:18][CH3:19])([OH:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:26]([CH2:27][CH3:28])[CH2:23][CH3:24])=[CH:8][CH:7]=1
Reactant: CCC(O)(c1ccc(OCCCBr)cc1)c1cccc(Cl)c1
Reactant: CCCNCCC
Product: CCN(CC)CCCOc1ccc(C(O)(CC)c2cccc(Cl)c2)cc1

Procedure:
19.2 g. of 3-chloro-4'-(3-bromopropoxy)-α-ethyl-benzhydrol and 51 ml. of dipropyl amine are refluxed for 8 hours, and the reaction mixture is then evaporated in vacuo. To the residue water is added and it is extracted with benzene. The benzene phase is washed with water, dried over anhydrous magnesium sulfate, and the solution is evaporated under reduced pressure. Distillation of the residue in vacuo yields 11.5 g. of the title compound, boiling at 203° to 206° C./13.3 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCCN1CCCCC1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1-(2-chloro-ethyl)-piperidine gave the title compound as white solid. MS: 424.1 (MH+, 2Cl).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][CH2:58][CH2:59][S:60]([CH3:63])(=[O:62])=[O:61])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].ClC1N=CC(O)=CN=1>CN(C)C=O.O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][CH2:58][CH2:59][S:60]([CH3:63])(=[O:62])=[O:61])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: Oc1cnc(Cl)nc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of 145 mg (0.224 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.7 ml of N,N-dimethylformamide, 130 mg (0.445 mmol) of 3-(methylsulfonyl)propyl p-toluenesulfonate and 135 mg (0.977 mmol) of potassium carbonate were added, and the mixture was stirred at 80° C. for 4 hours. 44 mg (0.337 mmol) of 2-chloro-5-hydroxypyrimidine was further added thereto, and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=55/45-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 137.0 mg of the title compound as a white solid (yield: 80%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH2:25][CH2:26][O:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(Br)cc2)cc1
Yield: 56.7 %

Procedure:
p-Bromobenzoic acid (6 g) and 3.35 g of triethylamine were dissolved in 80 ml of chloroform, the mixture was cooled at 0°-5° C. with stirring, and 3.26 g of ethyl chlorocarbonate was dropped thereinto. The mixture was stirred at the same temperature for 30 minutes, 5.86 g of methyl 4-(2-aminoethoxy)benzoate was added, and the mixture was stirred for 7 hours more. The reaction solution was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and with water, dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and 8.5 g of crystals obtained were recrystallised from ethyl acetate to give 6.4 g of the product, m.p. 134°-136° C.
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].Br[C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: [Zn+]c1ccccn1
Agent: [Br-]
Product: O=[N+]([O-])c1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure B was performed with 2-pyridylzinc bromide (4 mL, 2.0 mmol, 0.5 M in THF) and 3-bromo-4-chloro-nitrobenzene (236 mg, 1.0 mmol). Purified by chromatography on silica gel (10% ethyl acetate/hexanes) to yield 2-(2-chloro-5-nitrophenyl)pyridine as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[C:7]([I:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>ClC(Cl)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:17])(=[O:13])=[O:12])=[C:7]([I:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)O)c(I)c1
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Cl)c(I)c1
Temperature: 77.5 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a suspension of 100 (12.0 g; 35.0 mmol) in dichloroethane (300 mL) at 50° C. was added phosphorus pentachloride (11.01 g; 52.9 mmol). After addition was complete, the reaction mixture was heated at 75-80° C. overnight, cooled to 50° C., and additional phosphorus pentachloride (6.0 g; 28.8 mmol) was added. After heating at 85° C. for an additional 12 hours, the reaction mixture was again cooled to 50° C. and additional phosphorus pentachloride (2.0 g; 9.60 mmol) was added. Heating was continued at 90° C. for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting crude oil was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 20% v/v over 400 mL gradient elution) to give the title compound as a yellow oil (9.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:32][C:31](=[O:41])[CH:30]=2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[NH:32][C:31](=[O:41])[CH:30]=4)=[CH:25][CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
120 mg (purity 93%, 0.37 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate were reacted according to General Method 5A. Yield: 110 mg (53% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21](O)=[O:22])=[CH:15][C:14]=3[F:24])=[O:9])=[CH:4][CH:3]=1.C1COCC1.S(Cl)(Cl)=O.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>CN(C=O)C.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]([NH:42][CH2:41][C:40]2[CH:43]=[CH:44][C:37]([Cl:36])=[CH:38][CH:39]=2)=[O:22])=[CH:15][C:14]=3[F:24])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h

Procedure:
To a flask containing 3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid from Preparation No. 24 (0.11 g) and THF (3 mL) is added thionyl chloride (0.075 mL). The reaction mixture is stirred overnight then treated with one drop of DMF. After 4 hours, the reaction is concentrated under reduced pressure. The residue is triturated with toluene (2×) and dried in vacuo to afford a light yellow solid. The solid is dissolved in pyridine (2 mL), treated with p-chlorobenzylamine (0.04 mL), and a small amount of 4-dimethylaminopyridine is added. After stirring overinght, the reaction is concentrated under reduced pressure. The residue is triturated with toluene (3×) and dried in vacuo. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% MeOH:CH2Cl2 to 6% MeOH:CH2Cl2. The product-containing fractions are evaporated to give a solid which is crystallized from methanol:toluene to afford 0.04 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[C:11]([NH2:15])(=[O:14])[CH2:12][CH3:13]>>[NH:8]1[C:7]2=[C:2]([NH:15][C:11](=[O:14])[CH2:12][CH3:13])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: Clc1nccc2cc[nH]c12
Reactant: CCC(N)=O
Product: CCC(=O)Nc1nccc2cc[nH]c12
Yield: 15 %

Procedure:
N-(1H-pyrrolo[2,3-c]pyridin-7-yl)propanamide (Intermediate 8, yield: 15%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using propanamide.
Reaction SMILES: NC1N=C(N[C@H:9]2[CH2:13][C@@H:12]([CH2:14][OH:15])[C@H:11]([OH:16])[C@@H:10]2[OH:17])C(N=NC2C=CC(Cl)=CC=2)=C(Cl)N=1.NC1C=CC=CC=1>>[OH:15][CH2:14][CH:12]1[CH:11]([OH:16])[CH:10]([OH:17])[CH2:9][CH2:13]1
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)n1
Solvent: Nc1ccccc1
Product: OCC1CCC(O)C1O

Procedure:
Compound 1, (1S,2R,3S,5S)-3-[[2-amino-6-chloro-5-phenylazo]-4-pyrimidinyl]amino]-5-(hydroxymethyl)-1,2-cyclopentanediol was prepared by the same method used for Compound 11, using a stoichiometric amount of aniline instead of 4-chloroaniline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([NH:8][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncc([N+](=O)[O-])cc1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of 2,3-Diamino-5-nitropyridine (3) in dry pyridine (85 mL) was added 4-nitrobenzoylchloride (0.875 g, 4.7 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was then poured into H2O (250 mL) and stirred for 30 minutes. The resulting yellow solid was collected by filtration and rinsed with H2O until no pyridine remained. The solid was dried in vacuuo at 80 C to give 6 as a yellow solid (1.15 g, 3.8 mmol, 81%). 1H NMR (500 MHz, DMSO-d6) δ10.12 (br s, 1H), 8.83 (d, J=2.55 Hz, 1H), 8.84 (d, J=8.5 Hz, 2H), 8.35 (d, J=2.45 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H), 7.62 (br s, 2H). EIMS M−1 302.3.
Reaction SMILES: [C:1]([O:9][CH:10]([P:12]([O:48]C)([O:14][C@@H:15]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:17])=[O:13])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C.C(OC(P(O)(OC(NC(OCC1C=CC=CC=1)=O)CCCCC([C@]1(C(OCC2C=CC=CC=2)=O)CCCN1)=O)=O)C)(=O)C1C=CC=CC=1.CO>CC(C)=O.C(Cl)Cl.C(O)(=O)C>[C:1]([O:9][CH:10]([P:12]([OH:48])([O:14][C@@H:15]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:17])=[O:13])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)OC(=O)c1ccccc1
Agent: CC(OC(=O)c1ccccc1)P(=O)(O)OC(CCCCC(=O)[C@]1(C(=O)OCc2ccccc2)CCCN1)NC(=O)OCc1ccccc1
Agent: CN(C)C
Solvent: CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(OC(=O)c1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
The phenylmethyl ester product from part (c) (1.0 g.) in acetone (10 ml.) is saturated with trimethylamine and heated in a sealed tube at 75°-80° for 16 hours. The reaction mixture is evaporated and the residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and concentrated in vacuo to yield 0.82 g. of 1-[(S)-2-[[[1-(benzoyloxy)ethyl]hydroxyphosphinyl]oxy-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester. TLC (silica gel; methanol:acetic acid:methylene chloride, 1:1:20) Rf =0.21.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A round bottom flask equipped with magnetic stirrer and nitrogen inlet was charged with 2,4-dichlorobenzaldehyde (1.75 g, 10.0 mmol), acetone (44.1 ml, 0.60 mol) and water (20 ml). The mixture was cooled to 0° C. and a solution of sodium hydroxide (0.44 g, 11.0 mmol) in water (20 ml) was added drop wise during 1 hour to the vigorous stirred suspension. The reaction mixture was stirred for an additional 1.0 hour. The reaction mixture was concentrated in vacuo, poured onto 10% HCl (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (350 g) (eluent: n-hexane/ethyl acetate 1:1) to afford 1.9 g (88% of theory) of (E)-4-(2,4-dichloro-phenyl)-but-3-en-2-one in form of a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])(O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>[Zn].C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN(C)C(=O)CC1C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A flask is charged with 2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 19) (10.0 g, 30.8 mmol), acetic acid (250 mL), acetic anhydride (100 g), and Zn-dust (20 g). The mixture is kept under reflux, until all of the starting material is consumed (3 h). The solids are then filtered off, and from the filtrate the solvent is removed to leave an oil which crystallizes to a pale brown solid on treatment with di-iso-propyl ether. Yield of the title compound: 9.2 g (96.8%). 1H-NMR (CDCl3, 300 MHz) δ 2.73 (dd, 1, 2J=16.5 Hz, J=9.4 Hz, CH2NMe2); 3.00, 3.01 (2 s, 6, N(CH3)2); 3.20 (dd, 1, J=3.2 Hz, CH2NMe2); 4.06 (dd, 1, H-3); 4.90, 4.97 (AB, 2, 2J=15.6 Hz, CH2N); 6.70 (d, 1, J=7.9 Hz, H-7); 6.97 (“dtr”, J=7.5 Hz, J=1.2 Hz, H-5); 7.13 (“dtr”, J=7.8 Hz, J=1.2 Hz, H-6); 7.22-7.29, 7.29-7.33 (m, 5, 5 Ph-H); 7.38 (br d, 1, J=7.5 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.25 (CH2NMe2); 36.07, 37.51 (N(CH3)2); 42.59 (C-3); 44.28 (NCH2Ph); 109.12 (C-7); 122.66 (C-5); 124.85 (C-4); 127.49 (Ph meta-C); 127.71 (Ph para-C); 128.04 (C-6); 128.92 (Ph ortho-C); 129.63 (C-9); 136.19 (Ph ipso-C); 143.52 (C-8); 170.00 (CONMe2); 178.02 (C-2).
Reaction SMILES: [CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:8](=O)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)/[C:8](=[N:27]/[NH:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1- butyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.98 (t, 3H), 1.38 to 1.45 (m, 4H), 1.67-1.73 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.97 (br s, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:20][CH:19]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NC(C)(C)C)ncnc23)c1F
Yield: 6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid (Intermediate-60, 188 mg, 0.69 mmol), thionyl chloride (1 mL), and DIPEA (238 mg, 1.80 mmol) in THF (2 mL) to afford 13 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.69 (d, 1H), 8.50 (s, 1H), 8.37 (t, 1H), 8.15 (d, 1H), 7.52-7.40 (m, 4H), 4.32 (d, 2H), 1.55 (s, 9H), 1.03 (d, J=6.3 Hz, 6H); MS [M+H]+: 474.34.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:44])[CH2:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])=[O:10])[CH2:2]1.[CH:45](=O)[CH2:46][CH3:47]>>[CH2:45]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:44])[CH2:24][C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])=[O:10])[CH2:2]1)[CH2:46][CH3:47]
Reactant: CCC=O
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-N-((3S)-3-piperidylmethyl)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide and propionaldehyde. The product was obtained as a white solid.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C[O:8][C:9](=O)[CH:10]([CH3:25])[CH2:11][NH:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([NH:12][CH2:11][CH:10]([CH3:25])[C:9]([NH2:2])=[O:8])[CH:22]=1
Reactant: COC(=O)C(C)CNc1cc(OC)c2ccccc2n1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(NCC(C)C(N)=O)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A slurry of ammonium chloride (0.38 g, 7.11 mmol) in dry methylene chloride (20 mL) at 0° C. was treated with trimethylaluminum (1 eq, 7.11 mmol, 3.6 mL of a 2M solution in toluene). The mixture was allowed to warm to room temperature over a period of two hours, at which time a solution of 3-(4-methoxy-quinolin-2-ylamino)-2-methyl-propionic acid methyl ester (0.33 eq, 2.37 mmol, 0.65 g) in dry methylene chloride (5 mL) was added. The solution stirred at room temperature for two hours, then was quenched slowly by addition of concentrated HCl (1 mL). After stirring for an additional 30 minutes, the mixture was diluted with 10% NaOH (30 mL) and brine (20 mL) and extracted into methylene chloride. The organic extracts were dried over Na2SO4, filtered and concentrated to an oil. Purification via column chromatography on silica (95:5 methylene chloride/methanolic ammonia) provided the product (0.29 g, 48%) as a white solid. [M+H]+ 260.