Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[NH:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:8][CH2:7]1.CS(O[CH2:32][CH2:33][C@:34]1([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)[O:38][CH2:37][N:36]([C:39](=[O:54])[C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)[CH2:35]1)(=O)=O>C(#N)C>[F:52][C:50]([F:51])([F:53])[C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=1)[C:39]([N:36]1[CH2:35][C@@:34]([CH2:33][CH2:32][N:6]2[CH2:11][CH2:10][C:9]3([C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C@@H:12]3[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:8][CH2:7]2)([C:55]2[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=2)[O:38][CH2:37]1)=[O:54]
Reactant: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCNCC2
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(F)cc2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Sodium hydrogencarbonate (7.15 g, 85.11 mmol) was added to a solution of the crude product (32.1 g) obtained in Example 1h and the compound (37.6 g, 70.9 mmol) obtained in Example 1d in acetonitrile (160 mL) with stirring at room temperature, and the mixture was stirred at reflux temperature under a nitrogen atmosphere for 14 hours. The reaction mixture was left to stand for cooling to room temperature, and then the organic solvent was evaporated under reduced pressure. An aqueous sodium hydrogencarbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1→0:1, v/v) to give the title compound (47.8 g; yield, 93%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[P:23]([O-:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][C:18]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[N:17][CH:16]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1ccc(Br)nc1
Reactant: CCOP([O-])OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)OC(C)(C)C)c2ccccc2)cn1
Yield: 86 %

Procedure:
To tert-butyl (6-bromopyridin-3-yl)(phenyl)methylcarbamate (4-e) (3.4 g, 9.4 mmol), diethyl phosphite (1.55 g, 11.27 mmol) and Et3N (1.14 g, 11.27 mmol) in THF was added PdCl2(dppf) (200 mg). The mixture was heated at reflux under nitrogen overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified over silica gel (DCM/MeOH=20/1) to provide the product, 4-f (3.4 g, 86%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12](Cl)=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([O:24][CH3:25])(=[O:23])[CH:20]([CH3:22])[OH:21]>O1CCCC1>[CH2:3]([O:10][C:11]1[C:12]([O:21][CH:20]([C:19]([O:24][CH3:25])=[O:23])[CH3:22])=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)O
Reactant: Cc1ncc(OCc2ccccc2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1nc(C)ncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride is added to a mixture of 5-benzyloxy-4-chloro-2-methylpyrimidine, methyl lactate and tetrahydrofuran at 0° C. The mixture is stirred at room temperature for 1 hour, then, stirred at 90° C. for 30 minutes. The reaction solution was cooled to room temperature and poured into ice water, and extracted with ethyl acetate. The organic layer is washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13]2([CH3:23])[CH3:22]>ClCCl>[C:5]([C:18]1[CH:19]=[C:10]([Br:9])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:20])([CH3:21])[CH2:14][C:13]2([CH3:23])[CH3:22])(=[O:7])[CH3:6]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
A stirred, cooled (ice bath) suspension of aluminum chloride (0.99 g, 7.46 mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl chloride (0.58 g, 7.46 mmol). After 5 minutes, a solution of 6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.73 mmol)in dichloromethane was added. The reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was then poured into ice containing 10% hydrochloric acid and extracted with diethyl ether (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow oil (0.95 g, 83%). It was used as such for the next step without any characterization.
Reaction SMILES: [O-]CC.[K+:4].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH2:15]([N:22]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:33]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[C:27](/[CH:29]=[C:6](\[O-:8])/[C:5]([O:12][CH2:13][CH3:14])=[O:11])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[K+:4]
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)/C([O-])=C/c1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a suspension of potassium ethoxide (2.21 g, 26.3 mmol) in diethyl ether (20 mL) was added diethyl oxalate (3.57 mL, 26.3 mmol) under a nitrogen atmosphere. The reaction exhibited a slight exotherm and the reaction mixture was stirred for 20 min. The heterogeneous mixture became a homogeneous orange solution and then became a heterogeneous thick slurry and the stirring was ceased. In a separate container 2-(dibenzylamino)-5-nitro-4-methylpyridine (8.76 g, 26.3 mmol) was diluted with diethyl ether (14.3 mL) to give a suspension. The suspension was added to the slurry obtained above. The mixture was manually stirred using a glass rod, then sonicated for 20 min resulting in a thick black heterogeneous solution. The reaction mixture was allowed to stand under a nitrogen atmosphere overnight. The resulting solid was collected by filtration and rinsed with diethyl ether to give potassium (1Z)-1-[2-(dibenzylamino)-5-nitropyridin-4-yl]-3-ethoxy-3-oxoprop-1-en-2-olate (9.5 g, 76%) as a deep red solid: 1H NMR (300 MHz, CD3OD) δ1.17 (3H, t, J=7.0 Hz), 3.58 (2H, q, J=6.9 Hz), 4.82 (4H, s), 7.22-7.32 (11H, m), 8.74 (1H, s), 8.80 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][C:13]([NH2:15])=[O:14]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][C:13]([NH2:15])=[O:14])[N:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)CBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc([N+](=O)[O-])n1
Yield: 47.3 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 150 mg, 1.33 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (58 mg, 1.46 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, bromoacetamide (201 mg, 1.46 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2-(3-nitro-pyrazol-1-yl)-acetamide (107 mg, 48%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[N:16]1([CH2:21][CH2:22][CH2:23]N)[CH:20]=[CH:19][N:18]=[CH:17]1.[Cl-].[NH4+]>>[CH3:15][C:5]1[C:6]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=2[CH2:2][N:3]([CH2:23][CH2:22][CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[N:4]=1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: NCCCn1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1=NN(CCCn2ccnc2)Cc2cc3ccccn3c21
Temperature: 25 °C

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, eight equivalents of 3-(1H-imidazol-1-yl)propylamine and one equivalent of ammonium chloride under reflux in a nitrogen atmosphere for 1 hour and at room temperature for 48 hours gave the title compound as the free base after removal of excess amine in vacuo and purification by flash chromatography (silica gel, 10 to 40% methanol in ethyl acetate). The free base was converted to the dihydrochloride salt (methanol/ethereal HCl/diethyl ether), mp 162°-163° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=O.C([O:23][C:24](=O)[C:25](=[O:35])[CH2:26][C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:15]([C:14]4[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=4)[C:26]([C:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:25]([OH:35])[C:24]3=[O:23])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CCCCC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: O=C(C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(Cl)c(Cl)c1)C1CCCCC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 3,4 Dichlorobenzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclohexyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[C:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)=[C:9]([N+:26]([O-:28])=[O:27])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]>C(OCC)(=O)C.C1CCCCC1>[CH:29]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[C:9]([N+:26]([O-:28])=[O:27])[CH:8]=1)=[O:6])([CH3:31])[CH3:30]
Reactant: COC(=O)c1ccc(-c2c([N+](=O)[O-])cc(C(=O)N(C(C)C)C(C)C)cc2[N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)N(C(=O)c1cc([N+](=O)[O-])c(-c2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1)C(C)C
Yield: 103.4 %

Procedure:
Using the procedure of Example 19, Stage C, 244.4 mg of product B prepared in Example 19, Stage B were reacted to obtain 244.5 mg of the expected product with a Rf=0.146 (cyclohexane/ethyl acetate 1/1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][O:40][Si](C(C)C)(C(C)C)C(C)C)[C:30]=2[F:51])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:52]#[N:53])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[C:1]([O:5][C:6](=[O:54])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:51])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:52]#[N:53])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reaction time: 4 h
Yield: 125.9 %

Procedure:
To a mixture of [2-cyano-5-({[5-ethyl-2-fluoro-3-(2-triisopropylsilanyloxyethoxy)phenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzyl]carbamic acid t-butyl ester (56 mg) and THF (4 mL) there was added a 1M THF solution of tetrabutylammonium fluoride (0.147 mL). The mixture was stirred for 4 hours, and then ethyl acetate (50 mL) and water (50 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (50 mL) and once with saturated aqueous sodium chloride (50 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate and the solvent in the filtrate was distilled off under reduced pressure to obtain the target compound (56 mg) as a colorless oil.
Reaction SMILES: [SH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(O)=O.[C:26](=O)([O-:28])[O-:27].[K+].[K+].O>CN(C=O)C>[C:26]([C:2]([S:1][CH2:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)[C:3]([O:5][CH3:6])=[O:4])([OH:28])=[O:27]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(S)Cc1ccc(C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(C)cc1)(SCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of methyl 2-mercapto-3-(4-methylphenyl)propionate (17.5 g) in DMF (30 ml) was added dropwise to a mixture of α-bromophenylacetic acid (17.0 g), potassium carbonate (34.4 g) and DMF (120 ml), followed by stirring for an hour at room temperature. The reaction mixture was poured into water (300 ml) and extracted with ether. The aqueous layer was acidified with conc. HCl and extracted with ether. The ethereal layer was washed with water, dried (MgSO4) and concentrated to give methyl 2-(carboxy)(phenyl)methylthio-3-(4-methylphenyl)propionate (25.7 g, 90%) as an oil.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:6][NH:7][C:8](=[NH:10])S.OCC[NH:14]C.CS.[CH:18]([OH:21])(C)[CH3:19]>C(O)C>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[OH:21][CH2:18][CH2:19][N:7]([CH3:6])[C:8]([NH2:10])=[NH:14]
Reactant: CNC(=N)S
Reactant: CC(C)O
Reactant: CNCCO
Agent: CS
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN(CCO)C(=N)N

Procedure:
The above intermediate N-(2-hydroxyethyl)-N-methylquanidine sulfate was prepared as follows: A mixture containing 83.6 g of methyl isothiourea sulfate and 90 g of N-(2-hydroxyethyl)methylamine was heated on a steam bath under vacuum until no more methyl mercaptan was evolved. The solid remaining was boiled successively with hot isopropyl alcohol, hot absolute ethanol and then ether, and collected to yield 91 g of crystalline N-(2-hydroxyethyl)-N-methylguanidine sulfate.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1>>[CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH:20][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Product: O=C(Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2)C1CC1
Yield: 103.8 %

Procedure:
Prepared from N2-cyclooctyl-4H-benzo[d][1,3]oxazine-2,6-diamine (150 mg, 0.55 mmol) and and cyclopropane carboxylic acid (64 mg, 0.62 mmol) according to the procedure described for example 93. Obtained the title compound as a brown solid (195 mg, 99%), MS (ISP) m/e=342.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1O[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=1[Cl:23].[NH+]1C=CC=CC=1.CC1C=CC([S:37](O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[S:37]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=1[Cl:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3ccccc3s2)c(Cl)c1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
A mixture of 2-chlorobenzoxazole (489 mg, 2.88 mmol) and methyl 4-amino-3-chlorophenylacetate (567 mg, 2.84 mmol) and pyridinium•p-toluenesulfonate (pyridinium•p-toluenesulfonate (PPTS)) (214 mg, 0.85 mmol) was heated under reflux for 3 hours in xylene (10 ml). After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, methyl (4-(2-benzothiazolyl)amino-3-chlorophenyl)acetate (296 mg, 32%) was obtained as a white solid.
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([CH3:29])[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH:14]=2)=[CH:9][CH:8]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:33])=O>ClCCl>[CH3:29][N:20]([CH2:19][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:2][C:3]([Cl:33])=[O:4])=[CH:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=1)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)O
Solvent: ClCCl
Product: CN(Cc1cccc(-c2ccc(CCC(=O)Cl)cc2)c1)C(=O)c1ccccc1

Procedure:
By reacting 1.6 g (4.1 mmol) of 2-methyl-3-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-yl)propionic acid with 390 μl (4.5 mmol) of oxalyl chloride in dichloromethane, and after evaporation, 1.7 g (100%) of 3-(3′-{[methyl-(1-phenylmethanoyl)-amino]methyl}biphenyl-4-yl)propionyl chloride are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1.C(O[C:17](=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:30])N(OC)C)[CH2:21][CH2:20]1)(C)(C)C.[O:32]1[C:37]2[CH:38]=[CH:39][C:40](C=O)=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1>>[O:32]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:17][NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([C:8]4[S:9][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=5[N:7]=4)=[O:30])[CH2:23][CH2:24]3)=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1ccc2ncsc2c1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: COc1ccc2nc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)sc2c1

Procedure:
Using 6-methoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellowish solid (92 mg).
Reaction SMILES: C([O-])(=O)C.[K+].N[C@@H]1C2C(=CC=CC=2)C[C@H]1NC(C1NC2C(C=1)=CC(Cl)=CC=2)=O.C(O)(C(F)(F)F)=O.[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][C@@H:49]1[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]1[NH:58][CH2:59][C@@H:60]1[CH2:64][O:63]C(C)(C)[O:61]1)=[O:47])=[CH:40]2>CO.C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][C@@H:49]1[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]1[NH:58][CH2:59][C@@H:60]([OH:61])[CH2:64][OH:63])=[O:47])=[CH:40]2
Reactant: CC1(C)OC[C@@H](CN[C@@H]2c3ccccc3C[C@H]2NC(=O)c2cc3cc(Cl)ccc3[nH]2)O1
Agent: CC(=O)[O-]
Agent: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NC[C@@H](O)CO)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
2,3-O-(S)-Isopropylidene-L-glyceraldehyde (98 mg, 0.75 mmol) and potassium acetate (75 mg, 0.75 mmol) were added to a solution of N-{(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide (Method 5, 328 mg, 0.75 mmol) in MeOH (10 mL). The reaction was stirred at ambient temperature for approximately 5 mins then macroporous triethylammonium methyl polystyrene cyanoborohydride (352 mg, 0.9 mmol) was added and the reaction stirred at ambient temperature for a further 5 h. The reaction was then filtered and the volatiles were removed by evaporation under reduced pressure to 5-chloro-N-[(1R,2R)-1-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)-2,3-dihydro-1H-inden-2-yl]-1H-indole-2-carboxamide which was used crude in the next stage. TFA (3 mL) was added to a solution of 5-chloro-N-[(1R,2R)-1-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)-2,3-dihydro-1H-inden-2-yl]-1H-indole-2-carboxamide (100 mg, 0.23 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 24 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (90 mg, 100%) as a white solid.
Reaction SMILES: Cl.[C:2]([NH2:6])(=O)[CH2:3][CH3:4].[CH3:7][O:8][CH:9]([O:17]C)[C:10]([C:13](OC)=O)=[CH:11][O-].[Na+].C[N:21](C)C=O>>[CH2:3]([C:2]1[N:6]=[CH:13][C:10]([C:9]([O:8][CH3:7])=[O:17])=[CH:11][N:21]=1)[CH3:4]
Reactant: CCC(N)=O
Reactant: CN(C)C=O
Reactant: COC(=O)C(=C[O-])C(OC)OC
Agent: Cl
Agent: [Na+]
Product: CCc1ncc(C(=O)OC)cn1
Temperature: 100 °C

Procedure:
N-(4-chlorophenyl)-N-{(2S,4R)-1-[(2-ethylpyrimidin-5-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide was prepared following general procedure H, substituting 2-ethylpyrimidine-5-carbonyl chloride for 6-trifluoromethyl nicotinyl chloride. (2-ethylpyrimidine-5-carbonyl chloride was prepared in four steps. To a solution of 3,3-dimethoxypropionate in ethylene glycol dimethyl ether was added sodium hydride at 0° C., then methyl formate. The reaction mixture was warmed up to 50° C. for 30 m. and then stirred at room temperature for 20 h. Anhydrous diethyl ether was added and the precipitate was filtered to give sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate. To a solution of propionamide hydrochloride in dimethylformamide was added preformed sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate. Reaction mixture was heated to 100° C. for 1 h. to give methyl 2-ethylpyrimidine-5-carboxylate. Hydrolysis of the ester with sodium hydroxide gave 2-ethylpyrimidine-5-carboxylic acid. Subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF afforded 2-ethylpyrimidine-5-carbonyl chloride in decent yield). The rest of the procedures were followed as indicated in general procedure H to afford N-(4-chlorophenyl)-N-{(2S,4R)-2-methyl-1-[(2-ethylpyrimidin-5-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-4-yl}acetamide.