Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(OC([NH:22][C@@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:24]([OH:39])[C@@H:25]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26]([OH:28])=[O:27])=O)(C)(C)C.Cl>ClCCl.CO.C(OCC)C>[NH2:1][C@@:2]1([C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[NH2:22][C@@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:24]([OH:39])[C@@H:25]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26]([OH:28])=[O:27]
Reactant: COc1ccc(CN[C@@H](C(=O)O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: NC(=O)[C@]1(N)c2ccccc2C[C@H]1O
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN[C@@H](C(=O)O)[C@@H](O)[C@@H](N)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 g of 4(S)-tert-butoxycarbonylamino-3(S)-hydroxy-2(R)-(4-methoxybenzyl-amino)-5-phenyl-pentanoic acid 1(S)-amino-2(R)-hydroxyindan-amide (compound of Example 1) are dissolved in a mixture of 20 ml of dichloromethane and 4 ml of methanol. 300 ml of a 3 N solution of HCl in diethylether are added and the mixture is stirred for 3 hours at room temperature. The white precipitate is filtered off, washed with diethylether and dried in vacuo. The title compound is obtained in dihydrochloride salt form (m.p.: 147°-151°).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1>C(O)C>[CH2:6]([O:5][C:1](=[O:4])[CH:2]([N:18]1[CH2:17][CH2:16][N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[CH2:20][CH2:19]1)[CH3:3])[CH3:7]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C)N1CCN(c2cccc(Cl)c2)CC1
Reaction time: 0.67 h

Procedure:
Over a period of 40 minutes, 108 ml of ethyl acrylate are added to 38.3 g of N-(3-chlorophenyl)piperazine dissolved in 300 ml of anhydrous ethanol and 0.5 ml of Triton B. The temperature reaches 40° C. when addition is complete. After heating at reflux for 3 hours, the reaction mixture is concentrated in vacuo and the residue is distilled. 139 g of 4-(3-chlorophenyl)piperazin-1-ylpropionic acid ethyl ester are obtained, b.p/0.33 mmHg=176°-179° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([SH:7])[S:5][CH:6]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29][S:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1csc(S)n1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of 4-methylthiazole-2-thiol (0.32 g, 2.5 mmol) in anhydrous DMF (8.4 mL) add sodium hydride (0.10 g, 2.6 mmol, 60% dispersion in mineral oil) in portions at room temperature. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.74 g, 2.2 mmol) in anhydrous DMF (5.6 mL). Heat the reaction mixture at 45° C. for 2 h under nitrogen atmosphere, cool to room temperature and stir overnight. Quench the reaction mixture with 10% aqueous NaHCO3 (14 mL) and extract the mixture three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc (1:0 to 85:15 gradient over 30 min; 35 mL/min) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.753 g, 79%) as a white foam.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:33]([Cl:43])[CH:32]=5)[O:28][N:27]=4)=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:33]([Cl:43])[CH:32]=4)[O:28][N:27]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC(N)(CO)CO)no2)cc1Cl
Yield: 56 %

Procedure:
When the product of Step E was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 56% yield. 1H-NMR (DMSO-d6) 0.87 (tr, 3H, J=5.91 Hz); 1.31-1.4 (m, 4H); 1.72-1.77 (m, 2H); 2.98 (s, 2H); 3.24-3.35 (m, 8H); 4.14 (tr, 2H, J=6.18 Hz); 4.6 (m, 2H); 6.75 (d, 1H, J=7.74 Hz); 7.12 (tr, 1H); 7.23 (d, 1H, J=7.71 Hz); 7.34 (d, 1H, J=8.7 Hz); 8.1 (broad s, 1H); 8.4 (d, 1H, J=8.61 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[O:7][C:8]([CH3:27])([CH3:26])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:24])[CH2:18][C:19](OCC)=[O:20])=[CH:13][C:12]3=[O:25])[C:5]=2[CH:4]=1)#[N:2].[BH4-].[Na+].Cl>O1CCOCC1>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[O:7][C:8]([CH3:26])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:24])[CH2:18][CH2:19][OH:20])=[CH:13][C:12]3=[O:25])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC(O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C=C(n2ccc(C(O)CCO)cc2=O)c2cc(C#N)ccc2O1
Yield: 67.1 %

Procedure:
In 50 ml of dioxane, is dissolved 3.87 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-2-ethoxycarbonylethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 31. Then, 50 ml of an aqueous solution containing 3.71 g of sodium borohydride is added at room temperature and reacted at room temperature for one hour. After stopping the reaction by adding 100 ml of 2M aqueous hydrochloric acid, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/10 mixture of methanol/methylene chloride as a developing solvent. Thus, 2.32 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1,3-dihydroxypropyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30]>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: CN(C)CC(=O)O
Product: CN(C)CC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 56 using tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (206 mg, 0.57 mmol) and N,N-dimethylglycine (65 mg, 0.63 mmol) as starting materials.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].O>CS(C)=O.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][C:1]#[N:2])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
0.22 g of dibenzo-18-crown-6-ether and 1.57 g of sodium cyanide were suspended in 20 ml of DMSO, and 5.00 g of 4-tert-butylbenzyl bromide was dropwise added thereto with cooling with water. After having been stirred overnight at room temperature, the resulting mixture was further stirred at 50° C. for 5 hours. After this was left to be at room temperature, water was added thereto and extracted with ether. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 1.19 g of 4-tert-butylphenylacetonitrile was obtained from the fraction eluted with n-hexane:ethyl acetate=5:1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[C:16]([O:21]C)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>C(O)(C)(C)C>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:19][CH:18]=[CH:17][C:16]([OH:21])=[O:20])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C=O)c1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(C=CC=CC(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of potassium tert-butoxide (68 g) and tert-butanol (130 ml) was treated dropwise with a mixture of 3-methylbenzaldehyde (33.8 g) and methyl crotonate (45 ml). The temperature of the reaction mixture rose to 65° C. during the addition and this was maintained for a further 3 hours. The reaction mixture was cooled to room temperature, poured into ice/water and washed with diethyl ether. The aqueous phase was acidified with concentrated HCl and extracted with diethyl ether. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by trituration with isohexane and filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH2:38][CH2:39][CH3:40]>C(OCC)(=O)C>[CH2:37]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[CH2:31][NH:30][C:13]([C:4]1[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=[C:2]([Cl:1])[CH:3]=1)=[O:15])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN1CCCC1CN
Reactant: CN1CCSc2c(C(=O)O)cc(Cl)cc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCN1CCCC1CNC(=O)c1cc(Cl)cc2c1SCCN2C

Procedure:
To a solution of 1.8 g of 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.05 g of triethylamine, and then added 0.891 g of pivaloyl chloride dropwise with stirring at -10° C. to -5° C. followed by stirring the mixture at the same temperature for 30 minutes. To the resultant mixture was added 1.39 g of 2-aminomethyl-1-butylpyrrolidine at --10° C. to -5° C. and then stirred at room temperature for an hour. After the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated, the residue thus obtained was crystallized from diisopropyl ether. The crystals were collected by filtration and recrystallized from diisopropyl ether to give N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxamide as colorless crystals. Melting point: 108°-109° C.
Reaction SMILES: [CH:1]1([C:4]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH3:5])[CH2:3][CH2:2]1.CC(C(C1C2C(=C(CS(C)=[O:52])C=CC=2)NC=1)C1C=CC(C(F)(F)F)=CC=1)CC#N>>[CH:1]1([C:4]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:52])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Reactant: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 273 mg (0.81 mmol) of the compound from Example 95 in analogy to the synthesis of the compound from Example 91. 213 mg (73% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH3:27])[CH:25]=2)[N:20]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:19]1=[O:35])[CH3:17].[H-].[Na+].C([O-])(O)=O.[Na+]>COCCOC>[CH2:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH3:27])[CH:25]=2)[N:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:2]3[N:3]=[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]4[C:10]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:30][CH:29]=2)[C:19]1=[O:35])[CH3:17]
Reactant: CCOC(=O)c1c(Cl)nc2ccccn12
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C)cc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1c(Oc2ccc(-n3c(=O)n(CC)c4cc(C)cnc43)cc2)nc2ccccn12
Temperature: 50 °C
Yield: 12.1 %

Procedure:
The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (504 mg), 1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (302 mg) and NaH (67.3 mg) in DME (4 mL) was heated at 50° C. for 1 h. The mixture was heated at 200° C. for 3 h under microwave irradiation. The mixture was poured into sat. NaHCO3, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (62.0 mg) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=5)=[CH:32][C:27]4=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=5)=[CH:32][C:27]4=[N:26][CH:25]=3)=[CH:22][CH:23]=2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:51]([CH3:50])(=[O:53])=[O:52])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCOS(C)(=O)=O)n1
Yield: 97 %

Procedure:
In a round bottomed flask dissolve 1-[5-tert-butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-urea (0.2 g, 0.34 mmol) and triethyl amine (0.48 mL, 10 equiv.) in DCM (20 mL) under N2. Add methanesulfonyl chloride (0.13 mL, 4.8 equiv.) dropwise and stir the reaction at room temperature for 15 minutes. Load the crude reaction directly onto silica gel and purify (EtOAc to 5% MeOH: DCM) to give a yellow solid (0.22 g, 97%). MS (ES), m/z 665 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.ClC(Cl)(Cl)[C:34]([N:36]=C=O)=[O:35]>N1C=CC=CC=1>[C:34]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([CH3:31])=[CH:4]4)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])(=[O:35])[NH2:36]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(N)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy)quinazoline (60 mg, 0.14 mmol), (prepared as described for the starting material in Example 12), was dissolved in pyridine (3 ml) and cooled to 0° C. Trichloroacetyl isocyanate (17 μl, 0.14 mmol) was added and the mixture stirred for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at ambient temperature overnight and then at 50° C. for 2 hours. The solvent was removed under reduced pressure. Column chromatography of the residue (2% to 5% methanol/dichloromethane) gave 7-[(2S)-1-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (40 mg, 69%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][S:16]([O-:18])=[O:17].[Na+]>CS(C)=O>[CH3:15][S:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])(=[O:18])=[O:17]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 130 °C
Yield: 57.9 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzotrifluoride (2.09 g, 10 mmol) and sodium methanesulfinate (1,32 g, 11 mmol) in DMSO (20 mL) was heated at 130° C. for 17.5 hours. After cooling down to room temperature, the mixture was poured into ice-water. The whole was extracted with ethyl acetate (30 mL×2), the combined organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from hexane to give the subtitle compound (1.56 g, 57.8%, yield).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=2)[CH:21]=1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:31])[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1ccc(-c2cc(Br)ccc2F)cc1Cl
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C#N)c(Cl)c4)c3)cnc2c1F
Yield: 7 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol and 5′-bromo-3-chloro-2′-fluorobiphenyl-4-carbonitrile were coupled in the same way as in Example 6 to give 3-chloro-2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbonitrile as an off-white solid (20 mg, 7%): δH (400 MHz, d6-DMSO) 1.59 (6H, s), 7.33 (1H, t, J 7), 7.63 (1H, dd, J 11 and 9), 7.80-7.89 (2H, m), 7.96 (1H, dd, J 7 and 2), 8.03 (1H, s), 8.11-8.14 (2H, m), 8.53 (1H, d, J 7); m/z (ES+) 424 [MH+].
Reaction SMILES: Cl[C:2]1[S:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[C:3]=1[CH3:14].[CH3:15][N:16]([CH3:20])[C:17](=[S:19])[SH:18].[Na].[I-].[Na+]>C(O)C>[CH3:15][N:16]([CH3:20])[C:17]([S:19][C:2]1[S:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[C:3]=1[CH3:14])=[S:18]
Reactant: CN(C)C(=S)S
Reactant: Cc1c(Cl)sn(-c2ccccc2)c1=O
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1c(SC(=S)N(C)C)sn(-c2ccccc2)c1=O

Procedure:
To a solution of 4.51 g. (0.02 mole) of 5-chloro-4-methyl-2-phenyl-4-isothiazolin-3-one in 30 ml of warm ethanol was added a solution of 3.58 g. (0.02 mole) of N,N-dimethyldithiocarbamic acid, sodium salt dihydrate in 20 ml of ethanol followed by 0.1 g. of sodium iodide. The mixture was stirred several hours, cooled and filtered. The solid was triturated with water and dried to give 5.3 g. (88%) of the named product, mp 158°-160°.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.CCOCC>[CH3:32][S:33]([O:20][CH2:19][C:17]1[CH:18]=[C:13]([CH2:12][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:11])[C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CO)cc(Cl)c1Cl)C1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(COS(C)(=O)=O)cc(Cl)c1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl{[2,3-dichloro-5-(hydroxymethyl)phenyl]methyl}carbamate (1 eq.) from the previous step in dichloromethane (0.1 M) was added sequentially at 0 Hunig's base (3 eq.) and methanesulfonyl chloride (1.1 eq.). The resulting solution was stirred at 0° C. for 30 min and then at RT for 15 min. The reaction mixture was then diluted with ether and carefully quenched with 1 N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 29c (577 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue, compound 29d, was dried under reduced pressure for 18 h and was used without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[K+].[I-].[Na+].[Cl-].Cl[CH2:31][CH2:32][NH+:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>CS(C)=O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[C:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[N:10]([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:11]=2)[CH2:3][CH2:2]1
Reactant: ClCC[NH+]1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)c[nH]2)CC1
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
Combine tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (101.10 g, 301.39 mmol) and freshly ground potassium hydroxide (50.73 g, 3.0 eq) in dimethyl sulfoxide (500 mL). Stir for 15 minutes, then add sodium iodide (49.69 g, 1.1 eq). Add a solution of 1-(2-chloro-ethyl)-pyrrolidinium chloride (66.64 g, 1.3 eq) in dimethyl sulfoxide (1.01 L) and stir for four hours at room temperature. Pour the contents of the reaction into an ice/water mixture (˜1 L) and extract with methyl tert-butyl ether. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by HPLC (Chiralpak AD basic, hexane/ethanol 9:1) to give tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (82.0 g, 63%). MS (ES) m/z=433 [M]+.