Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:8](=[O:9])([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:14](=[O:17])[CH:15]=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: C=CC(=O)OCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 2.26 g (90%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.80 (4 H, m, CH2 --CH2), 1.86 (3 H, d, J=5 Hz, CH3), 4.24 (4 H, m, 2×CH2 --O), 5.7-6.6 (4 H, m, CH=CH2 and CH).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:15]1[CH2:19][C:18]([CH2:21][OH:22])([CH3:20])[O:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([C:15]1[CH2:19][C:18]([CH:21]=[O:22])([CH3:20])[O:17][N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1(CO)CC(C(C)(C)C)=NO1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C=O)CC(C(C)(C)C)=NO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 117.0 g (1.5 moles) of dimethylsulfoxide in 300 ml of dichloromethane was added dropwise to a solution of 83.8 g (0.66 mole) of oxalyl chloride in 750 ml of dichloromethane at -60° C. The reaction mixture was stirred for 15 minutes at this temperature, after which 102.6 g (0.6 mole) of 3-tert-butyl-5-hydroxymethyl-5-methylisoxazoline were added and stirring was continued for a further 15 minutes. After the dropwise addition of 303.6 g (3.0 moles) of triethylamine, the mixture was stirred for a further 10 minutes and was heated to 25° C. and 1.8 l of water were added. After 10 minutes, the organic phase was separated off, the aqueous phase was extracted with twice 600 ml of dichloromethane and the combined organic phases were washed with three times 450 ml of a 1N hydrochloric acid and once with 450 ml of a saturated sodium carbonate solution, dried and evaporated down. 100 g of a yellow liquid were obtained, this liquid being subjected to fractional distillation under 0.2 mbar.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[CH3:35][C@H:36]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[C:37]([O:39]C1C=CC([N+]([O-])=O)=CC=1)=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:53]([O:52][C:50]([NH:49][C@H:36]([C:37]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:39])[CH3:35])=[O:51])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(N)=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(N)=O

Procedure:
A sample of compound XV (4.3 g, 9 mmole) was hydrogenated as described in the previous paragraph and the partially deblocked peptide (RfC, 0.60) was acylated with Z-L-Ala-ONp (3.47 g, 10 mmole, Bachem) in the presence of DIEA (3.2 ml, 20 mmole) and HOBt (1.3 g, 9 mmole). The product isolated as described for XV weighed 4.2 g (85%) m.p. 214°-217° C., [α]D24 -9.5° (c 0.8, DMF); RfB, 0.48; RfI, 0.33.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>ClCCl.O>[F:22][C:21]([F:24])([F:23])[S:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1)(=[O:19])=[O:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2ccoc2c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2ccoc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a stirred solution of benzofuran-6-ol (17.0 g, 127 mmol) in pyridine (20 g, 254 mmol) and dichloromethane (200 mL) was added Tf2O (53.7 g, 190 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford a crude product that was purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford benzofuran-6-yl trifluoromethanesulfonate (30.0 g, 88.0% yield). 1H NMR (300 MHz, CDCl3) δ: 7.72 (d, J=2.1, 1H), 7.67 (d, J=8.7, 1H), 7.48 (d, J=1.5, 1H), 7.19 (dd, J=8.7, 2.1, 1H), 6.82-6.91 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11]([N+:15]([O-:17])=[O:16])[C:10](OS(O)(=O)=O)=[CH:9][C:8]=2[Cl:23])(=[O:3])[CH3:2].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=1)=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:9][C:8]=2[Cl:23])(=[O:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)c1c(C)c2c([N+](=O)[O-])c(OS(=O)(=O)O)cc(Cl)c2[nH]c1=O
Product: CC(=O)c1c(NCc2ccc(Cl)cc2)c2c([N+](=O)[O-])ccc(Cl)c2[nH]c1=O
Yield: 57.1 %

Procedure:
3-Acetyl-8-chloro-4-methylsulfoxy-5-nitro-2-quinolinone (3.28g, 0.01 mol ) and p-chlorobenzylamine (1.42g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.32g, yield: 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30]Cl)[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:30][C:26]4[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[CH:28][N:27]=4)[CH:15]=3)[O:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)cc1
Reactant: COc1ccnc(CCl)c1
Product: COc1ccc(O[C@@H]2COc3ccc(OCc4cc(OC)ccn4)cc3[C@@H]2O)cc1

Procedure:
By the method of Example 13, the title product of Example 20 (494 mg, 3 mmol) and freshly prepared 4-methoxy-2-picolyl chloride (903 mg, 3 mmol) were converted to present title product, purified by chromatography on silica gel using 51:25:4 toluene:ethyl acetate:isopropanol as eluant and recrystallization from toluene, 564 mg; m.p. 80-82° C.; tlc Rf 0.3 (19:1 CH2Cl2 : isopropanol); exact mass calculated: 409.1531; found: 409.1530.
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30]>>[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:22]2[N:18]([CH3:17])[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:21]=2[CH3:23])=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CN=C(Cl)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN=C(c1ccc(Cl)cc1)c1c(C)cc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl 4-chlorobenzimidoyl chloride (6.07 g, 32.3 mmole), chlorosulfonic acid (0.46 g, 4.0 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (6.64 g, 39.8 mmole), and 70% perchloric acid (5.5 g, 38.3 mmole) to yield 9.3 g (69%) of a bright yellow solid, m.p. 168°-171° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C(N2CCCCC2)C1O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2C(N2CCCCC2)C1O
Yield: 93.6 %

Procedure:
0.14 g (0.44 mmol) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6-amino-7-nitro-2H-benzo[b]pyran were dissolved in 23.7 g of ethanol and hydroge gas was blown in the presence of 0.10 g of 5% palladiumcarbon, as a catalyst, for 3 hours at room temperature under one atmospheric pressure while stirring. The reaction liquid was filtered under suction to remove the catalyst therefrom, and the solvent was distilled off to obtain 0.12 g (yield: 95%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6-,7-diamino-2H-benzo[b]pyran as a dark red oil. As being unstable, this oil was directly used in the next diazotization.
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:32])([CH3:31])[CH2:21][C@:22]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH:24]=O)=[C:16]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:32])([CH3:31])[CH2:21][C@@:22]([C:26]([F:29])([F:28])[F:27])([OH:30])[CH2:23][C:24]#[CH:1])=[C:16]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:15]=1
Reactant: CC(C)(C[C@@](O)(CC=O)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC[C@](O)(CC(C)(C)c1ccc(Cl)cc1S(C)(=O)=O)C(F)(F)F
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a stirred solution of (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (12.5 g, 0.065 mol) and (R)-5-(4-chloro-2-methanesulfonylphenyl)-3-hydroxy-5-methyl-3-trifluoromethylhexanal (20.5 g, 0.054 mol) in 150 mL of dry MeOH was added potassium carbonate (13.8 g, 0.100 mol) at room temperature. The reaction was stirred overnight. The reaction was diluted with 200 mL of water and extracted with diethyl ether. The organic layers was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo. The crude material was eluted through a plug of silica using 20-25% diethyl ether/hexanes to provide (S)-6-(4-chloro-2-methanesulfonylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (18.5 g, 89%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].Br[CH2:38][C:39]([CH3:41])=[CH2:40]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([CH2:16][CH2:17][C:18]1([CH3:23])[O:19][CH2:20][CH2:21][O:22]1)[CH2:40][C:39]([CH3:41])=[CH2:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: CC1(CCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)OCCO1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)C[C@H](CCC1(C)OCCO1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-2 (18 g, 54 mmol) in tetrahydrofuran (400 mL) at −78° C. under argon was added a solution of lithium bis(trimethylsilylamide) (70.2 mL of a 1.0 M solution in tetrahydrofuran) over 20 min. After an additional 20 min., 3-bromo-2-methylpropene (14.6 g, 108 mmol) was added in one portion. After 20 min., the reaction mixture was allowed to warm to 0° C. After 3.5 h, the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil (3-1) was used without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[C:7]=2[OH:22])[S:12][N:13]=1
Reactant: CCOC(=O)c1ncc2snc(-c3ccccc3F)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1ncc2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 348.1 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][N:12]=[C:11]([CH3:14])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:13][N:12]=[C:11]([CH3:14])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cc(C2(O)CCC(=O)CC2)sn1
Product: Cc1cc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)sn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(3-methyl-isothiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.N>>[NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Yield: 84.7 %

Procedure:
(S)-2-(1-((5-(5-Amino-6-methoxypyridin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (63 mg, 0.10 mmol) was treated with trifluoroacetic acid (1.4 mL, 18.17 mmol) and a solution of ammonia (7N in methanol, 1.4 mL, 9.8 mmol) at room temperature for 2 h according to the method described in Example 27 to give 43 mg (85% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[NH2:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1c([N+](=O)[O-])cnc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(N)cnc2ccccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A solution of 4-methyl-3-nitroquinoline (500 mg, 2.66 mmol) in conc. HCl (10 mL) was heated to 50° C. Tin (II) chloride dihydrate (1.5 g, 6.6 mmol) was added. The mixture was stirred at 50° C. overnight. The mixture was diluted with water (20 mL). The mixture was adjusted to pH 9 by addition of 5N aqueous sodium hydroxide. The mixture was cooled to 4° C. and extracted twice with ethyl acetate (30 mL). The combined extracts were washed with ice-cold water (40 mL) and dried over anhydrous Na2SO4, filtered, and concentrated to give 3-amino-4-methylquinoline (340 mg, 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.89-7.91 (m, 1H), 7.79-7.82 (m, 1H), 7.44-7.38 (m, 2H), 3.77 (br s, 2H), 2.37 (s, 3H).
Reaction SMILES: [C:1]1(C(C(C)C)CN)[CH:6]=CC=C[CH:2]=1.Cl.[C:14]1([CH:20](CC(C)C)[CH2:21][N:22]([CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH2:40][C:41](=[CH:45][C:46]([OH:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=2[Cl:34])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:34].[C:14]1([CH:20]([CH:1]([CH3:6])[CH3:2])[CH2:21][N:22]([CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH2:40][C:41](=[CH:45][C:46]([OH:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[C:25]=2[Cl:34])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C(CN)c1ccccc1
Reactant: CC(C)CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Agent: Cl
Product: CC(C)C(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1

Procedure:
The titled compound was prepared from 2-phenyl-3-methylbutylamine (Acta. Pharmaceutica Nordica (1992), 4(2), 105-9) in the same manner as the preparation of N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine, hydrochloride, Example 189e-h. MS (ESI) 548 (MH+).
Reaction SMILES: [CH2:1]=O.[C:3]([CH2:5][C:6]([OH:8])=[O:7])#[N:4].C(=O)=O.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH2:1][C:5](=[CH2:6])[C:3]#[N:4])[CH3:14].[C:3]([CH2:5][C:6]([OH:8])=[O:7])#[N:4]
Reactant: CNC
Reactant: C=O
Agent: N#CCC(=O)O
Agent: O=C=O
Product: C=C(C#N)CN(C)C
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Aqueous formaldehyde (162 ml, 37%) was added slowly to a solution of cyanacetic acid (85g) and dimethylamine (350 ml, 26% aqueous). The solution was stirred at 15° C during the addition and then at 40° C for a further 30 minutes. Carbon dioxide evolution commenced at 31° C, the rate of evolution increasing with rising temperature. The solution was extracted with ether (3 × 250 ml), after drying over anhydrous sodium sulphate, the solvent was evaporated at atmospheric pressure to give an oil. The infrared spectrum of the oil showed two nitrile peaks (2240cm-1 and 2220cm-1) indicating the pressure of two compounds. Distillation of the mixture gave 2-dimethylaminomethylacrylonitrile (25g, 23%, boiling point 43° C/1.0mm) and 1,3-bis(dimethylamino) propane-2-nitrile (43g, 31% boiling point 57° C/0.8mm).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[O:10][C:11]([C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.O>CCO>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:20][C:18]2[N:19]=[C:14]([C:11]3[O:10][C:9]([C:8]4[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=4)=[N:13][CH:12]=3)[CH:15]=[CH:16][CH:17]=2)[CH:26]=1
Reactant: COc1ncccc1-c1ncc(-c2cccc(Nc3cc(C)ccn3)n2)o1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc[nH]c4=O)o3)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of {6-[2-(2-methoxy-pyridin-3-yl)-oxazol-5-yl]-pyridin-2-yl}-(4-methyl-pyridin-2-yl)-amine above (236 mg, 0.655 mmol) in EtOH (10 ml) was treated with conc. HCl (1 ml) and heated to 80° C. for 3 h and then 60° C. for 18 h. The cooled mixture was treated with water and the product precipitated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.78 (s, 1H), 8.29-8.22 (m, 1H), 8.11 (d, J=5.0 Hz, 1H), 7.86 (s, 1H), 7.82-7.73 (m, 2H), 7.69-7.63 (m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 6.77 (d, J=5.0 Hz, 1H), 6.40 (t, J=6.7 Hz, 1H), 2.35 (s, 3H). (ESI+) m/z 346 (M+H)+. Retention time=2.02 mins (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:41]=[S:42]1(=[O:54])[CH2:47][CH2:46][CH:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:52][CH2:53][N:48]([CH:45]4[CH2:44][CH2:43][S:42](=[O:41])(=[O:54])[CH2:47][CH2:46]4)[CH2:49][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 749.63 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl>CN(C=O)C.COCCOC>[C:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:8]1[C:9](=[O:10])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[N:6]=[C:7]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCCC(=O)OC(C)(C)C)c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, a solution of 130 mg (0.38 mmol) of the compound from Example 222A in 1 ml DMF and 2 ml DME at 0° C. is treated with 505 μl of an LiHMDS solution (1 M in THF, 505 μmol). The cooling bath is removed and the mixture stirred for 15 mins at RT before addition of 113 mg (505 μmol) of tert.-butyl 4-bromobutanoate. The mixture is stirred overnight at 70° C. After cooling, 0.5 ml of 1 N hydrochloric acid are added. The reaction mixture is then directly separated by preparative HPLC (Method 20). 48 mg (30% of theory) of the title compound are obtained.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[CH2:11][CH2:12][OH:13])=[C:6]([N+:15]([O-])=O)[CH:5]=1>O.CCOC(C)=O.[Fe]>[NH2:15][C:6]1[CH:5]=[C:4]([Br:3])[CH:9]=[CH:8][C:7]=1[N:10]([CH3:14])[CH2:11][CH2:12][OH:13]
Reactant: CN(CCO)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(CCO)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 76.3 %

Procedure:
Iron (1.5 g, 26.2 mmol) and ammonium chloride (0.39 g, 1.0 eq) in water (8 mL) was heated to reflux for 0.5 hours, 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethanol (25B) (2.0 g, 7.27 mmol) was slowly added. The reaction mixture was heated to reflux for 14 hours, cooled to rt, diluted with water and EtOAc and filtered through Celite. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 60:40-40:60, to provide 1.36 g (76%) of the desired product 2-((2-amino-4-bromophenyl)(methyl)amino)ethanol (25C): 1H NMR (300 MHz, CDCl3) δ 6.92-6.82 (3H, m), 3.68 (2H, t), 3.04 (2H, t), 2.70 (3H, s).