Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[O:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: NC1CCOCC1
Product: C(#Cc1cnc(NC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=280.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine(example 1, step 2) and tetrahydro-pyran-4-ylamine
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(Br)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(Br)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
Ethyl 5-bromosalicylate (299 mg), 4-chloro-6,7-dimethoxyquinoline (270 mg), and 4-dimethylaminopyridine (440 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (40 mg, yield 8%).
Reaction SMILES: [CH3:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[C:20]([N:22]([CH3:24])[CH3:23])=O>CN(C=O)C>[CH3:20][N:22]([CH3:24])/[CH:23]=[CH:1]/[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1/C=C/N(C)C
Temperature: 100 °C
Yield: 25.4 %

Procedure:
A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice-water and the precipitated solid was filtered and washed with water to give (E)-ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate (11 g, 48%)
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([CH2:9][OH:10])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:10][CH2:9][C@@H:8]1[CH2:7][CH2:6][C:3]2([CH2:5][CH2:4]2)[N:2]1[CH3:1])(=[O:21])=[O:20]
Reactant: CN1[C@H](CO)CCC12CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1[C@H](COS(C)(=O)=O)CCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2 g, 1.42 mmol) and triethylamine (0.287 g, 2.84 mmol, Shantou Xilong chemical factory) in 5 mL of dichloromethane was stirred at 0° C. for 30 min. To the mixture was added methanesulfonyl chloride (0.325 g, 2.84 mmol, Shanghai Haiqu chemical. Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 4 hrs and quenched with a mixture of 5 mL of saturated Na2CO3 aqueous solution and 5 mL of water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate as yellow oil (150 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[N:23]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:30](=[O:31])[CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)CN1CCOCC1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: O=C(CN1CCOCC1)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and morpholin-4-yl-acetic acid; MS: m/e=421.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.[CH:30](OCC)=[O:31]>>[Cl:29][C:22]1[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[CH:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([CH:30]=[O:31])[CH2:4]4)[CH:9]=3)[CH:11]=2)[NH:16][CH:17]=1)[CH3:20]
Reactant: CCOC=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C=O)C4)c3)cc12
Temperature: 50 °C

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol) and ethyl formate (2 mL) was heated to 50° C. overnight in a sealed tube. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.3 Hz, 3 H), 4.37 (ddd, J=6.2, 5.1, 4.9 Hz, 1 H), 4.46-4.54 (m, 1 H), 4.60 (dd, J=9.2, 5.4 Hz, 1 H), 4.71 (t, J=8.6 Hz, 1 H), 5.30 (q, J=7.3 Hz, 1 H), 5.38 (tt, J=8.2, 5.5 Hz, 1 H), 7.16-7.23 (m, 1 H), 7.38 (d, J=1.3 Hz, 1 H), 7.39-7.57 (m, 2 H), 7.72 (s, 1 H), 7.95 (s, 1 H), 8.07 (s, 1 H), 8.33 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 458.06 (100) [MH+]. HPLC: tR=3.22 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12].ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:34])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12]
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) of the compound from Example 8 were introduced into 15 ml of dichloromethane at 0° C., 61.9 mg (0.25 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 91 mg (88% of theory) of the title compound as mixture of diasteromers.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:17][C:18]1[N:19]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]#[N:34])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>ClCCl>[C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[S:17][C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:24][CH:25]=1)#[N:34]
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)Sc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (1.1 eq), followed by ethyl 2-bromo-2,2-difluoroacetate (1.05 eq) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (prepared as described herein, 1 eq) in dichloromethane and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M), 50% saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. Hexanes were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O.O1CCOCC1>[CH2:19]([O:18][C:16]([NH:15][CH2:14][C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:27])=[O:4])=[O:26])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccccc1NC(=O)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)O
Reaction time: 8 h

Procedure:
Lithium hydroxide (55 mg, 1.32 mmol) in water (0.8 mL), was added to a solution of the benzoate (1) (300 mg, 0.88 mmol) in dioxane (4 mL). After stirring overnight, the reaction mixture was concentrated at 40° C. to give a viscous oil, which was treated with 10% aqueous hydrochloric acid (3 mL), with the resulting emulsion formed being extracted with ethyl acetate (4×). The organic phases were combined, dried (MgSO4) and concentrated to give the title benzoic acid (2) quantitatively as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20].C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:21][C:18]=4[C:19]#[N:20])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: N#Cc1cc(F)ccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)ccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 59.6 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.199 g), 5-fluoro-2-(piperazin-1-yl)benzonitrile (0.203 g), triethylamine (0.110 g), and ethylene glycol (2 mL) give 0.218 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 179-180° C.; MS m/z 369; IR (mineral oil) 1494, 1329, 808, 1452, 1072 cm-1. 1H NMR (CDCl3) δ2.78, 3.20, 3.78, 6.99, 7.13, 7.19, 7.26, 7.51, 7.52.8.14.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[OH-].[NH4+:23].C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(Cl)(Cl)Cl.ClCCl>[NH2:23][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCO
Reactant: [NH4+]
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCO

Procedure:
4-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (7.27 g, 25.7 mmol, which can be prepared using the method described in Example 43 Part A) was oxidized and then animated using a modification of the general method described in Example 4 Part H. The oxidation was run in chloroform in lieu of dichloromethane and the crude N-oxide was isolated prior to being dissolved in dichloromethane and treated with ammonium hydroxide and toluene sulfonyl chloride. 3.82 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol was obtained.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]([C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:27]=[N:28][N:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:30]=3[CH3:31])=[O:25])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)#[N:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:9]([C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:27]=[N:28][N:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:30]=3[CH3:31])=[O:25])=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:14]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:15][CH2:16]1)#[N:10]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(CC(=O)C(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
1-Bromo-3,3-dimethylbutan-2-one (88 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 8.5 hours. Water was added to the reaction solution, the precipitated solid was filtered, and washed with water and ethanol to give the titled compound (271 mg) as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([NH2:27])=[CH:22][CH:23]=3)[CH2:18]2)[CH2:15][CH3:16])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl.CCN(C(C)C)C(C)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][N:14]([CH2:15][CH3:16])[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([NH:27][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:22][CH:23]=3)[CH2:18]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(N)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid isopropylamide (200 μL of 0.25 M in acetonitrile, 50 μmol) was added 220 μL of a 0.25 M solution of 4-fluorobenzoyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2 and concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile:water (0.1% TFA)) to afford 4-({ethyl-[7-(4-fluoro-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide (13.1 mg) 7 [M+H]+=495.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9](O)[C:10]([Cl:14])([Cl:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:10]([Cl:14])([Cl:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(Cl)(Cl)C(O)NC(=O)c1ccc(Br)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(Cl)(Cl)C(NC(=O)c1ccc(Br)cc1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-N-(2,2-dichloro-1-hydroxybutyl)benzamide 119 (0.84 g, 2.48 mmol) in chloroform (15 mL) was reacted with PCl5 (0.54 g, 2.46 mmol) at 50° C. for 30 minutes. The mixture was cooled to room temperature and quenched with ice. The aqueous layer was extracted with ether. The organic solution was dried over MgSO4, filtered, and reacted with 4-chloroaniline (0.66 g, 5.17 mmol). The mixture was stirred for 18 hours at room temperature. An acidic, (HCl) aqueous workup and ether extraction preceded chromatographic purification on silica gel (7:3 hexane:CH2Cl2). 4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)butyl)benzamide (Compound-15) was obtained as a white solid (701 mg, 62%). 1H NMR (300 MHz, CDCl3): δ=7.64-7.56 (m, 4H), 7.16 (d, J=9.0 Hz, 2H), 6.73 (d, J=8.7 Hz, 2H), 6.48 (d, J=9.6 Hz, 1H), 6.01 (d, J=9.0 Hz, 1H), 2.50-2.27 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].[N:42]12[CH2:49]C[CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1(C)C=CC=CC=1.CC(O)C.CC(O)C.CC(O)C.CC(O)C.[Ti]>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][C@@H:38]1[CH:45]2[CH2:46][CH2:47][N:42]([CH2:43][CH2:44]2)[CH2:49]1)=[O:36]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Ti]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 34 %

Procedure:
To a refluxing solution of methyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.33 g, 0.59 mmol) and (R)-3-quinuclidinol (0.3 g, 2.4 mmol) in toluene (5 mL), was added titanium(IV)-i-propoxide (0.173 mL, 0.59 mmol, d=0.97). After refluxing for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound (0.13 g, 34%); 1H NMR (DMSO-d6): δ 1.31-1.34 (m, 1H), 1.51-1.55 (m, 4H), 1.78-1.88 (m, 3H), 1.98-2.01 (m, 1H), 2.33 (t, 2H, J=7.2 Hz), 2.52-2.72 (m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.59-4.62 (m, 4H), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m, 2H), 10.80 (br, 1H); MS for C38H44N6O4 m/z 649.11 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>>[CH3:2][C:3]1[CH:8]=[C:7]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:30][CH2:29][N:28]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)ccn1
Temperature: 50 °C
Yield: 25.2 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 2 mL) was added to a solution of (R)-tert-butyl 4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (example 372, step 1; 100 mg, 201 μmol). The reaction mixture was heated at 50° C. for 17 h, then partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in dichloromethane (5 mL), then cooled to 0° C. and treated with N,N-diisopropylethylamine (78 mg, 604 μmol) and methanesulfonyl chloride (34.6 mg, 302 μmol). The ice bath was removed, then after 3 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (24 mg, 25%). White foam, MS (ESI+): m/z=475.1 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[CH:9]=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>C(O)(=O)CC>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[C:9]1[C:15]2[NH:11][C:12]([C:9]([C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=3)=[C:12]3[N:11]=[C:15]([C:9]([C:3]4[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=4)=[C:12]4[NH:11][C:15](=[C:9]([C:3]5[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=5)[C:12]5[CH:13]=[CH:14][C:15]=1[N:11]=5)[CH:14]=[CH:13]4)[CH:14]=[CH:13]3)=[CH:13][CH:14]=2
Reactant: Cc1nc(C=O)n(C)c1C
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Cc1nc(-c2c3nc(c(-c4nc(C)c(C)n4C)c4ccc([nH]4)c(-c4nc(C)c(C)n4C)c4nc(c(-c5nc(C)c(C)n5C)c5ccc2[nH]5)C=C4)C=C3)n(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4,5-Trimethylimidazole-2-carboxaldehyde (37, 750 mg, 5.42 mmol), prepared according to literature procedure (Alcalde, E. et al., Tetrahedron 52:15171-15188 (1996)), was dissolved in propionic acid (120 mL) in a 250 mL three neck round-bottom flask equipped with a thermometer and a condenser. The solution was heated to reflux then pyrrole (0.38 mL, 5.42 mmol) was added. The reaction mixture was heated at reflux for an additional 5 h, then cooled to room temperature while exposed to air overnight. The propionic acid was removed by vacuum distillation yielding a dark solid residue which was adsorbed onto silica gel. Purification by column chromatography (gradient elution 5-10% MeOH/CH2Cl2) provided porphyrin 38 as a mixture of atropisomers (108 mg, 10.7%). 1H NMR (300 MHz, CDCl3)*−2.90, −2.85, −2.78 (3 s, 2H, atropisomer NH), 2.50 (s, 12 H), 2.57 (s, 12 H), 3.15-3.42 (multiple s, 12 H, atropisomer N—CH3), 8.91 (multiple s, 8 H, atropisomer).
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([O:14]C)=O)([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].C(Cl)Cl.C[Al](C)C>CCCCCC>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:12]([C:8]2[N:9]=[N:10][S:11][C:7]=2[CH2:6][O:5][Si:4]([CH:16]([CH3:17])[CH3:18])([CH:19]([CH3:20])[CH3:21])[CH:1]([CH3:2])[CH3:3])=[O:14])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)[Si](OCc1snnc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a cooled solution (0° C.) of methyl 5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboxylate (2.2 g, 0.0066 mol) and 3-chloro-4-fluoroaniline (1.5 g, 0.010 mol) in DCM (20 mL, 0.4 mol) was added 2.0 M of trimethylaluminum in hexane (12 mL) under nitrogen and stirred for 15 minutes. The volatiles were removed in vacuo and the crude was purified by flash chromatography to give the desired product (2.3 g, 78%). MF=C19H27ClFN3O2SSi; LCMS calculated for C19H28ClFN3O2SSi (M+H)+: m/z=444.1.